TINF2

Summary

TINF2 (TERF1 interacting nuclear factor 2, HGNC:11824) is a protein-coding gene on chromosome 14q12, encoding TERF1-interacting nuclear factor 2 (Q9BSI4). Component of the shelterin complex (telosome) that is involved in the regulation of telomere length and protection. It is a common-essential gene (DepMap: required in 98.8% of cancer cell lines).

This gene encodes one of the proteins of the shelterin, or telosome, complex which protects telomeres by allowing the cell to distinguish between telomeres and regions of DNA damage. The protein encoded by this gene is a critical part of shelterin; it interacts with the three DNA-binding proteins of the shelterin complex, and it is important for assembly of the complex. Mutations in this gene cause dyskeratosis congenita (DKC), an inherited bone marrow failure syndrome.

Source: NCBI Gene 26277 — RefSeq curated summary.

At a glance

• Gene–disease (curated): dyskeratosis congenita, autosomal dominant 3 (Definitive, ClinGen) — +5 more curated relationships
• GWAS associations: 2
• Clinical variants (ClinVar): 667 total — 15 pathogenic, 10 likely-pathogenic
• Phenotypes (HPO): 134
• Cancer dependency (DepMap): dependent in 98.8% of screened cell lines (common-essential)
• MANE Select transcript: NM_001099274

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11824
Approved symbol	TINF2
Name	TERF1 interacting nuclear factor 2
Location	14q12
Locus type	gene with protein product
Status	Approved
Aliases	TIN2
Ensembl gene	ENSG00000092330
Ensembl biotype	protein_coding
OMIM	604319
Entrez	26277

Gene structure

Transcript identifiers

Ensembl transcripts: 36 — 18 retained_intron, 14 protein_coding, 2 protein_coding_CDS_not_defined, 2 nonsense_mediated_decay

ENST00000267415, ENST00000399423, ENST00000557830, ENST00000557915, ENST00000557921, ENST00000558476, ENST00000558510, ENST00000558566, ENST00000558703, ENST00000559019, ENST00000559147, ENST00000559549, ENST00000646753, ENST00000699682, ENST00000699683, ENST00000699684, ENST00000699685, ENST00000699686, ENST00000699687, ENST00000699688, ENST00000699689, ENST00000699690, ENST00000699691, ENST00000699692, ENST00000699693, ENST00000699694, ENST00000699695, ENST00000699696, ENST00000699697, ENST00000699698, ENST00000699699, ENST00000699700, ENST00000699701, ENST00000911300, ENST00000943624, ENST00000943625

RefSeq mRNA: 3 — MANE Select: NM_001099274 NM_001099274, NM_001363668, NM_012461

CCDS: CCDS41936, CCDS41937, CCDS86378

Canonical transcript exons

ENST00000267415 — 9 exons

Exon	Start	End
ENSE00001193206	24240263	24240330
ENSE00001288575	24240419	24240875
ENSE00003466709	24239643	24239931
ENSE00003614965	24240064	24240155
ENSE00003662983	24241020	24241116
ENSE00003850978	24242141	24242623
ENSE00003977324	24241204	24241311
ENSE00003977346	24241675	24241776
ENSE00003977347	24241890	24241994

Expression profiles

Bgee: expression breadth ubiquitous, 144 present calls, max score 96.49.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 33.4274 / max 278.2121, expressed in 1822 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
142567	25.0755	1815
142563	3.5258	1491
142564	2.1606	1284
142562	1.1085	588
142566	0.8281	534
142568	0.4160	193
142565	0.3128	136

Top tissues by expression

144 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
granulocyte	CL:0000094	96.49	gold quality
right adrenal gland	UBERON:0001233	96.43	gold quality
right adrenal gland cortex	UBERON:0035827	96.37	gold quality
leukocyte	CL:0000738	96.31	gold quality
monocyte	CL:0000576	96.30	gold quality
left adrenal gland	UBERON:0001234	96.30	gold quality
left adrenal gland cortex	UBERON:0035825	96.09	gold quality
bone marrow cell	CL:0002092	95.96	gold quality
adrenal gland	UBERON:0002369	95.86	gold quality
blood	UBERON:0000178	95.71	gold quality
tonsil	UBERON:0002372	95.61	gold quality
lower esophagus mucosa	UBERON:0035834	95.55	gold quality
esophagus mucosa	UBERON:0002469	95.43	gold quality
esophagus	UBERON:0001043	94.71	gold quality
spleen	UBERON:0002106	94.62	gold quality
cortical plate	UBERON:0005343	94.61	gold quality
smooth muscle tissue	UBERON:0001135	94.31	gold quality
descending thoracic aorta	UBERON:0002345	94.26	gold quality
lymph node	UBERON:0000029	94.20	gold quality
right lung	UBERON:0002167	94.20	gold quality
upper lobe of left lung	UBERON:0008952	94.06	gold quality
left coronary artery	UBERON:0001626	94.05	gold quality
urinary bladder	UBERON:0001255	94.01	gold quality
omental fat pad	UBERON:0010414	93.98	gold quality
ganglionic eminence	UBERON:0004023	93.96	gold quality
embryo	UBERON:0000922	93.95	gold quality
lower esophagus muscularis layer	UBERON:0035833	93.94	gold quality
lower esophagus	UBERON:0013473	93.93	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	93.93	gold quality
adipose tissue	UBERON:0001013	93.89	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.77

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): NFKB, NR3C1, SP1, TBPL1

miRNA regulators (miRDB)

11 targeting TINF2, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-7-1-3P	99.91	71.53	4384
HSA-MIR-7-2-3P	99.91	71.40	4394
HSA-MIR-6499-3P	99.90	66.38	1212
HSA-MIR-944	99.82	70.85	3042
HSA-MIR-4519	99.48	66.10	859
HSA-MIR-3678-3P	99.31	67.10	1432
HSA-MIR-4477B	99.23	70.49	1733
HSA-MIR-4477A	98.83	69.75	2952
HSA-MIR-2467-3P	98.65	67.18	1969
HSA-MIR-374B-3P	98.63	68.24	1360
HSA-MIR-541-5P	98.24	67.77	1181

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 98.8% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 40)

• Co-localises with the interstitial TTAGGG repeats in interstitial telomeres. (PMID:11938440)
• Down-regulation of TRF1, TRF2 and TIN2 genes is important to maintain telomeric DNA for gastric cancers. (PMID:12530079)
• TIN2 alters the conformation of TRF1, which favours a tertiary telomeric structure that hinders telomerase from gaining access to telomeres (PMID:12835755)
• Partial knockdown of TIN2 by small hairpin RNA in a telomerase-positive cell line resulted in telomere elongation, which is typical of reduced TRF1 function. (PMID:15133513)
• TIN2 mutants defective in binding of TRF1 or TRF2 induce a DNA damage response and destabilize TRF1 and TRF2 at telomeres in human cells. (PMID:15292264)
• TIN2 binds TRF1 and TRF2 simultaneously and stabilizes the TRF2 complex on telomeres (PMID:15316005)
• May be involved in multistep hepatocarcinogenesis by playing crucial role in telomere shortening. (PMID:15632001)
• a novel extra-telomeric organization of TIN2 is associated with the control of cell proliferation; TIN2 is an important regulator of mammary epithelial differentiation (PMID:15741234)
• coordinated interactions among TPP1, TIN2, TRF1, and TRF2 may ensure robust assembly of the telosome, telomere targeting of its subunits, and, ultimately, regulated telomere maintenance (PMID:16880378)
• TINF2, a component of the shelterin telomere protection complex, is mutated in dyskeratosis congenita. (PMID:18252230)
• Results suggest that distinct TIN2 complexes exist and that TIN2-15C-sensitive subcomplexes are particularly important for cell survival in the absence of functional p53. (PMID:18443218)
• In a large series, TINF2 mutations account for approximately 11% of all patients with dyskeratosis congenita. (PMID:18669893)
• conclude that a significant proportion of patients who underwent unrelated donor hematopoietic stem cell transplantation for severe aplastic anemia harbored mutations in TINF2 and may have had occult dyskeratosis congenita (PMID:19090550)
• Our results suggest a dual role for TIN2 in mediating the function of the shelterin complex and tethering telomeres to the nuclear matrix. (PMID:19229133)
• The expression of TINF2 may work to reduce the telomere length in precancerous lesions and offer new insight into the mechanism of carcinogenesis in gastric cancer. (PMID:20127252)
• TIN2-anchored TPP1 plays a major role in the recruitment of telomerase to telomeres in human cells. (PMID:20404094)
• exon 6 of TINF2 natural mutations in 2/142 Japanese patients with acquired acquired bone marrow failure syndromes (PMID:20560964)
• TINF2 mutation of shelterin complex is associated with dyskeratosis congenita. (PMID:20979174)
• Frameshift or nonsense mutations in TIN2 gene having very short telomeres are found in patients with dyskeratosis congenita. (PMID:21199492)
• Mouse gene deletion experiments revealed DNA-damage-response pathways that threaten chromosome ends and how the components of the telomeric shelterin complex prevent activation of these pathways.[Shelterin] (PMID:21209389)
• The presence of dysfunctional telomeres in chronic lymphocytic leukemia did not correlate with telomere shortening or chromatin marks deregulation but with a down-regulation of 2 shelterin genes: ACD and TINF2. (PMID:21355086)
• Results suggests that the disruption of TIN2-TRF1 interaction may contribute to the severe dyskeratosis congenita phenotype observed in the context of the TIN2 truncation mutation. (PMID:21477109)
• TIN2 mutations in DC may compromise the telomere recruitment of telomerase, leading to telomere shortening and the associated pathogenesis. (PMID:21536674)
• These results demonstrate the important roles that Sp1 and NF-kappaB play in regulating the expression of the human telomere-binding protein TIN2. (PMID:21731707)
• The positive correlation between telomere length in dyskeratosis congenital and percent of LINE-1 methylation was restricted to TINF2 mutations. (PMID:21981348)
• Siah2 acts as an E3 ligase to directly ubiquitylate TIN2 in vitro. (PMID:22064479)
• results suggest a link between telomeric proteins (TIN2)and metabolic control, providing an additional mechanism by which telomeric proteins regulate cancer and aging (PMID:22885005)
• A potential mitotic regulation of TIN2 by phosphorylation, is reported. (PMID:23977114)
• Our findings identify TINF2 as a mutant telomere gene in familial pulmonary fibrosis and suggest that infertility may precede the presentation of pulmonary fibrosis in a small subset of adults with telomere syndromes (PMID:25539146)
• telomerase elongates telomeres at a reduced frequency in TIN2-R282H heterozygous cells; this recruitment defect is further corroborated by examining the effect of this mutation on telomerase-telomere co-localization. (PMID:26230315)
• data supports a mechanism whereby telomerase deficiency and subsequent shortened telomeres initiate a DNA damage response and create a pro-oxidant environment, especially in Dyskeratosis Congenita cells carrying TINF2 mutations (PMID:26859482)
• We report ophthalmic findings in twins with Revesz syndrome due to a previously unreported mutation in TINF2 and propose that phenotypic and molecular overlaps between DKC spectrum disorders and pediatric retinal vasculopathies may reflect a shared pathophysiologic basis. (PMID:28095086)
• demonstrate here the presence of a novel spliced isoform of TIN2 in chronic lymphocytic leukemia (CLL), related to deletion of exon 2 in the TIN2 gene (PMID:28575699)
• study suggests that, gallstone does not affect telomere length and even after having increased telomere length, decreased expression of some shelterin genes in inflamed tissue might cause telomeres to cap improperly, possibly leading to telomere dysfunction and further, gallbladder carcinogenesis (PMID:28643740)
• The TIN2 plays an important role in maintaining the stable shelterin complex required for proper telomere end protection. (PMID:29160297)
• In TRF1-TIN2-TRF2 complex, the peptide enhances the protein-protein interactions to yield a stable heterodimer (PMID:29428209)
• The C-Terminal Extension Unique to the Long Isoform of the Shelterin Component TIN2 Enhances Its Interaction with TRF2 in a Phosphorylation- and Dyskeratosis Congenita Cluster-Dependent Fashion. (PMID:29581185)
• Loss of RNA-binding protein HuR facilitates cellular senescence through posttranscriptional regulation of TIN2 mRNA. (PMID:29584879)
• Authors found that TPP1(ACD) upon binding to TIN2 induces changes that expand TIN2 binding capacity, such that TIN2 can accommodate both TRF1 and TRF2 simultaneously. Authors suggest a molecular model that explains why ACD is essential for the stable formation of TRF1-TIN2-TRF2 core complex. (PMID:31158366)
• All of the TIN2 isoforms stimulated telomerase to similar extents. Mutations in the TPP1 TEL patch abrogated this stimulation, suggesting that TIN2 functions with TPP1/POT1 to stimulate telomerase processivity. (PMID:31383750)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	zgc:113263	ENSDARG00000045842
danio_rerio	tinf2	ENSDARG00000054473
mus_musculus	Tinf2	ENSMUSG00000007589
rattus_norvegicus	Tinf2	ENSRNOG00000020189

Protein

Protein identifiers

TERF1-interacting nuclear factor 2 — Q9BSI4 (reviewed: Q9BSI4)

Alternative names: TRF1-interacting nuclear protein 2

All UniProt accessions (12): Q9BSI4, A0A8V8TNM3, A0A8V8TNM8, A0A8V8TNU6, A0A8V8TP44, A0A8V8TQ07, A0A8V8TQE2, B4DFJ1, H0YKA6, H0YL20, H0YLC9, H0YMN3

UniProt curated annotations — full annotation on UniProt →

Function. Component of the shelterin complex (telosome) that is involved in the regulation of telomere length and protection. Shelterin associates with arrays of double-stranded TTAGGG repeats added by telomerase and protects chromosome ends; without its protective activity, telomeres are no longer hidden from the DNA damage surveillance and chromosome ends are inappropriately processed by DNA repair pathways. Plays a role in shelterin complex assembly. Isoform 1 may have additional role in tethering telomeres to the nuclear matrix.

Subunit / interactions. Monomer. Found in a complex with POT1; TERF1 and TNKS1. Component of the shelterin complex (telosome) composed of TERF1, TERF2, TINF2, TERF2IP ACD and POT1. Interacts with TERF1, TERF2 and ACD.

Subcellular location. Nucleus. Chromosome. Telomere Nucleus matrix.

Tissue specificity. Detected in heart, brain, placenta, lung, liver, skeletal muscle, kidney and pancreas.

Disease relevance. Dyskeratosis congenita, autosomal dominant, 3 (DKCA3) [MIM:613990] A rare multisystem disorder caused by defective telomere maintenance. It is characterized by progressive bone marrow failure, and the clinical triad of reticulated skin hyperpigmentation, nail dystrophy, and mucosal leukoplakia. Common but variable features include premature graying, aplastic anemia, low platelets, osteoporosis, pulmonary fibrosis, and liver fibrosis among others. Early mortality is often associated with bone marrow failure, infections, fatal pulmonary complications, or malignancy. The disease is caused by variants affecting the gene represented in this entry. Dyskeratosis congenita, autosomal dominant, 5 (DKCA5) [MIM:268130] A disease characterized by bone marrow hypoplasia, nail dystrophy, fine sparse hair, fine reticulate skin pigmentation, oral leukoplakia, bilateral exudative retinopathy, cerebellar hypoplasia, and growth retardation. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The TBM domain mediates interaction with TERF1.

Isoforms (3)

UniProt ID	Names	Canonical?
Q9BSI4-1	1, TIN2L	yes
Q9BSI4-2	2, TIN2S
Q9BSI4-3	3

RefSeq proteins (3): NP_001092744, NP_001350597, NP_036593 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR029400	TINF2_N	Domain
IPR039098	TINF2	Family

Pfam: PF14973

UniProt features (37 total): helix 10, sequence variant 6, cross-link 4, sequence conflict 4, splice variant 3, mutagenesis site 2, short sequence motif 2, modified residue 2, initiator methionine 1, chain 1, region of interest 1, strand 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
3BQO	X-RAY DIFFRACTION	2
3BU8	X-RAY DIFFRACTION	2.15
5XYF	X-RAY DIFFRACTION	2.2

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9BSI4-F1	61.42	0.28

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (6): 353, 2, 295, 302, 306, 341

Mutagenesis-validated functional residues (2):

Position	Phenotype
258	abolishes interaction with terf1.
262	does not effect interaction with terf1.

Function

Pathways and Gene Ontology

Reactome pathways

14 pathways

ID	Pathway
R-HSA-110328	Recognition and association of DNA glycosylase with site containing an affected pyrimidine
R-HSA-110329	Cleavage of the damaged pyrimidine
R-HSA-110330	Recognition and association of DNA glycosylase with site containing an affected purine
R-HSA-110331	Cleavage of the damaged purine
R-HSA-1221632	Meiotic synapsis
R-HSA-171306	Packaging Of Telomere Ends
R-HSA-171319	Telomere Extension By Telomerase
R-HSA-174411	Polymerase switching on the C-strand of the telomere
R-HSA-174414	Processive synthesis on the C-strand of the telomere
R-HSA-174417	Telomere C-strand (Lagging Strand) Synthesis
R-HSA-174430	Telomere C-strand synthesis initiation
R-HSA-174437	Removal of the Flap Intermediate from the C-strand
R-HSA-2559586	DNA Damage/Telomere Stress Induced Senescence
R-HSA-9670095	Inhibition of DNA recombination at telomere

MSigDB gene sets: 456 (showing top): GOBP_NEGATIVE_REGULATION_OF_EPITHELIAL_CELL_PROLIFERATION, GOBP_RNA_TEMPLATED_DNA_BIOSYNTHETIC_PROCESS, GOBP_CHROMOSOME_ORGANIZATION, GOBP_NEGATIVE_REGULATION_OF_TELOMERE_MAINTENANCE_VIA_TELOMERASE, PID_TELOMERASE_PATHWAY, GOBP_TELOMERE_CAPPING, REACTOME_MEIOTIC_SYNAPSIS, GOBP_TELOMERE_MAINTENANCE_VIA_TELOMERE_LENGTHENING, GOBP_TELOMERE_ORGANIZATION, GOBP_POSITIVE_REGULATION_OF_ORGANELLE_ORGANIZATION, KAUFFMANN_DNA_REPAIR_GENES, chr14q12, GOBP_NEGATIVE_REGULATION_OF_CELLULAR_COMPONENT_ORGANIZATION, GOBP_REGULATION_OF_TELOMERE_MAINTENANCE, RICKMAN_TUMOR_DIFFERENTIATED_WELL_VS_POORLY_DN

GO Biological Process (7): telomere capping (GO:0016233), telomere assembly (GO:0032202), positive regulation of telomere maintenance (GO:0032206), negative regulation of telomere maintenance via telomerase (GO:0032211), negative regulation of epithelial cell proliferation (GO:0050680), protein localization to chromosome, telomeric region (GO:0070198), regulation of telomere maintenance via telomere lengthening (GO:1904356)

GO Molecular Function (2): telomeric repeat DNA binding (GO:0042162), protein binding (GO:0005515)

GO Cellular Component (9): chromosome, telomeric region (GO:0000781), nuclear telomere cap complex (GO:0000783), nucleoplasm (GO:0005654), perinucleolar chromocenter (GO:0010370), nuclear matrix (GO:0016363), nuclear body (GO:0016604), shelterin complex (GO:0070187), nucleus (GO:0005634), chromosome (GO:0005694)

Reactome top-level categories

Rollup of top-8 pathways:

Category	Pathways
Telomere C-strand (Lagging Strand) Synthesis	3
Depyrimidination	2
Depurination	2
Telomere Maintenance	2
Extension of Telomeres	2
Meiosis	1
Processive synthesis on the C-strand of the telomere	1
Cellular Senescence	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
telomere maintenance	2
regulation of telomere maintenance	2
nuclear lumen	2
cellular anatomical structure	2
intracellular membraneless organelle	2
cellular component assembly	1
telomere organization	1
positive regulation of DNA metabolic process	1
positive regulation of chromosome organization	1
telomere maintenance via telomerase	1
regulation of telomere maintenance via telomerase	1
negative regulation of telomere maintenance via telomere lengthening	1
negative regulation of DNA biosynthetic process	1
negative regulation of cell population proliferation	1
epithelial cell proliferation	1
regulation of epithelial cell proliferation	1
protein localization to chromosome	1
telomere maintenance via telomere lengthening	1
sequence-specific DNA binding	1
binding	1
chromosomal region	1
telomere cap complex	1
nuclear protein-containing complex	1
chromocenter	1
nucleoplasm	1
nuclear telomere cap complex	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

1352 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TINF2	TERF2	Q15554	999
TINF2	TERF1	P54274	999
TINF2	ACD	Q96AP0	999
TINF2	POT1	Q9NUX5	999
TINF2	TERF2IP	Q9NYB0	998
TINF2	TPP1	O14773	994
TINF2	TNKS	O95271	956
TINF2	DKC1	O60832	944
TINF2	TERT	O14746	930
TINF2	CBX3	Q13185	917
TINF2	CTC1	Q2NKJ3	905
TINF2	NOP10	Q9NPE3	902
TINF2	DCLRE1B	Q9H816	896
TINF2	NHP2	Q9NX24	890
TINF2	RTEL1	Q9NZ71	884

IntAct

195 interactions, top by confidence:

A	B	Type	Score
TERF2IP	TERF2	psi-mi:“MI:0914”(association)	0.970
ACD	TINF2	psi-mi:“MI:0915”(physical association)	0.960
TINF2	ACD	psi-mi:“MI:0915”(physical association)	0.960
ACD	TINF2	psi-mi:“MI:0914”(association)	0.960
TINF2	TERF1	psi-mi:“MI:0915”(physical association)	0.940
TERF1	TINF2	psi-mi:“MI:0915”(physical association)	0.940
TINF2	TERF2	psi-mi:“MI:0915”(physical association)	0.890
TERF2	TINF2	psi-mi:“MI:0407”(direct interaction)	0.890
TERF2	TINF2	psi-mi:“MI:0914”(association)	0.890
POT1	TERF2	psi-mi:“MI:0914”(association)	0.890

BioGRID (222): TINF2 (Affinity Capture-Western), TINF2 (Reconstituted Complex), TERF2 (Affinity Capture-Western), TINF2 (Affinity Capture-Western), ACD (Two-hybrid), TINF2 (Affinity Capture-MS), FKBP5 (Affinity Capture-MS), GOLGA1 (Affinity Capture-MS), MRE11A (Affinity Capture-MS), PPP3R1 (Affinity Capture-MS), PRKDC (Affinity Capture-MS), TRIM27 (Affinity Capture-MS), TAF1 (Affinity Capture-MS), TERF1 (Affinity Capture-MS), TERF2 (Affinity Capture-MS)

ESM2 similar proteins: A0A1B0GVZ6, A5D7I0, A6H7B4, A6NDZ8, A6NE82, A6NJ08, A6NJB7, A6NJI1, A6NL46, A6QP24, A8MUA0, A8MUI8, A8MV72, A8MX80, B2RW88, O94850, P0C6A0, P24097, P50617, Q0P5M0, Q0VD86, Q2KIL8, Q3B8N5, Q3SY00, Q3SYA9, Q3UN58, Q5BMD4, Q5JTZ5, Q5RBE4, Q5VZ46, Q66MI6, Q68US1, Q6GQV0, Q6PAC4, Q80TS7, Q80VY2, Q8BFY7, Q8BII1, Q8IXW0, Q8K2F3

Diamond homologs: Q9BSI4, Q9QXG9

SIGNOR signaling

4 interactions.

A	Effect	B	Mechanism
RPS6KA3	unknown	TINF2	phosphorylation
TINF2	“form complex”	“Shelterin complex”	binding
SP1	“up-regulates quantity by expression”	TINF2	“transcriptional regulation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 103 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Processive synthesis on the C-strand of the telomere	5	51.4×	3e-06
Telomere C-strand (Lagging Strand) Synthesis	5	51.4×	3e-06
Removal of the Flap Intermediate from the C-strand	5	42.9×	5e-06
Telomere Extension By Telomerase	6	37.0×	3e-06
Polymerase switching on the C-strand of the telomere	5	28.6×	3e-05
Meiosis	6	23.1×	1e-05
Nuclear Envelope (NE) Reassembly	5	19.8×	2e-04
Reproduction	6	15.4×	8e-05

GO biological processes:

GO term	Partners	Fold	FDR
telomere maintenance via telomerase	5	38.2×	6e-05
positive regulation of telomere maintenance	5	26.6×	2e-04
glycolytic process	5	19.9×	6e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

667 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	15
Likely pathogenic	10
Uncertain significance	319
Likely benign	265
Benign	9

Top pathogenic / likely-pathogenic (25)

Variant ID	HGVS	Classification
1762219	NM_001099274.3(TINF2):c.815G>A (p.Trp272Ter)	Pathogenic
1763437	NM_001099274.3(TINF2):c.845_848dup (p.Thr284fs)	Pathogenic
31541	NM_001099274.3(TINF2):c.805C>T (p.Gln269Ter)	Pathogenic
31542	NM_001099274.3(TINF2):c.839del (p.Lys280fs)	Pathogenic
31543	NM_001099274.3(TINF2):c.811C>T (p.Gln271Ter)	Pathogenic
3238737	NM_001099274.3(TINF2):c.1A>G (p.Met1Val)	Pathogenic
3238738	NM_001099274.3(TINF2):c.591del (p.Trp198fs)	Pathogenic
37090	NM_001099274.3(TINF2):c.826del (p.Arg276fs)	Pathogenic
38922	NM_001099274.3(TINF2):c.849dup (p.Thr284fs)	Pathogenic
4056134	NM_001099274.3(TINF2):c.848_849dup (p.Thr284fs)	Pathogenic
4845227	NM_001099274.3(TINF2):c.850A>C (p.Thr284Pro)	Pathogenic
5624	NM_001099274.3(TINF2):c.838A>G (p.Lys280Glu)	Pathogenic
5625	NM_001099274.3(TINF2):c.845G>A (p.Arg282His)	Pathogenic
5626	NM_001099274.3(TINF2):c.844C>A (p.Arg282Ser)	Pathogenic
5627	NM_001099274.3(TINF2):c.844C>T (p.Arg282Cys)	Pathogenic
1879275	NM_001099274.3(TINF2):c.623C>G (p.Ser208Ter)	Likely pathogenic
2633179	NM_001099274.3(TINF2):c.857dup (p.Met286fs)	Likely pathogenic
2744816	NM_001099274.3(TINF2):c.869T>C (p.Phe290Ser)	Likely pathogenic
3237357	NM_001099274.3(TINF2):c.865C>G (p.Pro289Ala)	Likely pathogenic
3576544	NM_001099274.3(TINF2):c.848C>T (p.Pro283Leu)	Likely pathogenic
3771848	NM_001099274.3(TINF2):c.1044del (p.Ala349fs)	Likely pathogenic
38923	NM_001099274.3(TINF2):c.850A>G (p.Thr284Ala)	Likely pathogenic
38924	NM_001099274.3(TINF2):c.860T>C (p.Leu287Pro)	Likely pathogenic
4077696	NM_001099274.3(TINF2):c.399+1G>A	Likely pathogenic
444325	NM_001099274.3(TINF2):c.865C>T (p.Pro289Ser)	Likely pathogenic

SpliceAI

1468 predictions. Top by Δscore:

Variant	Effect	Δscore
14:24240501:T:TA	donor_gain	1.0000
14:24240502:C:A	donor_gain	1.0000
14:24240738:T:TA	donor_gain	1.0000
14:24241671:TCA:T	donor_loss	1.0000
14:24241673:A:AC	donor_gain	1.0000
14:24241674:C:CC	donor_gain	1.0000
14:24241674:CCTG:C	donor_gain	1.0000
14:24241674:CCTGC:C	donor_loss	1.0000
14:24241772:TTTGT:T	acceptor_gain	1.0000
14:24241773:TTGT:T	acceptor_gain	1.0000
14:24241774:TGT:T	acceptor_gain	1.0000
14:24241775:GT:G	acceptor_gain	1.0000
14:24241777:C:CC	acceptor_gain	1.0000
14:24241777:C:CG	acceptor_loss	1.0000
14:24241778:T:A	acceptor_loss	1.0000
14:24241780:T:C	acceptor_gain	1.0000
14:24241780:T:TC	acceptor_gain	1.0000
14:24241786:A:AC	acceptor_gain	1.0000
14:24241786:A:C	acceptor_gain	1.0000
14:24241789:C:CT	acceptor_gain	1.0000
14:24238587:A:AG	acceptor_gain	0.9900
14:24238588:G:GG	acceptor_gain	0.9900
14:24238588:GA:G	acceptor_gain	0.9900
14:24240152:CACA:C	acceptor_gain	0.9900
14:24240156:C:CC	acceptor_gain	0.9900
14:24240417:A:AC	donor_gain	0.9900
14:24240417:ACT:A	donor_gain	0.9900
14:24240418:C:CC	donor_gain	0.9900
14:24240418:CTC:C	donor_gain	0.9900
14:24240677:A:C	donor_gain	0.9900

AlphaMissense

2886 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
14:24241926:A:C	F87L	0.977
14:24241926:A:T	F87L	0.977
14:24241928:A:G	F87L	0.977
14:24241282:A:C	F143L	0.976
14:24241282:A:T	F143L	0.976
14:24241284:A:G	F143L	0.976
14:24241732:A:C	F114L	0.976
14:24241732:A:T	F114L	0.976
14:24241734:A:G	F114L	0.976
14:24242151:A:G	L61P	0.973
14:24242166:C:G	R56P	0.969
14:24242275:A:G	W20R	0.969
14:24242275:A:T	W20R	0.969
14:24241262:A:G	L150P	0.968
14:24241927:A:G	F87S	0.968
14:24242146:C:G	A63P	0.968
14:24241251:A:G	Y154H	0.964
14:24242155:C:G	G60R	0.964
14:24242163:A:T	L57H	0.964
14:24242240:A:C	F31L	0.963
14:24242240:A:T	F31L	0.963
14:24242242:A:G	F31L	0.963
14:24242163:A:G	L57P	0.958
14:24241235:T:A	E159V	0.957
14:24242167:G:T	R56S	0.957
14:24241238:A:G	L158P	0.956
14:24241733:A:G	F114S	0.956
14:24241283:A:G	F143S	0.954
14:24242187:A:T	V49D	0.954
14:24241255:A:C	F152L	0.952

dbSNP variants (sampled 300 via entrez): RS1000504150 (14:24239597 T>A), RS1001320214 (14:24243114 G>A), RS1002438747 (14:24241069 A>G), RS1002808441 (14:24244307 G>A), RS1002974518 (14:24240520 T>G), RS1003145871 (14:24243850 C>G,T), RS1003240383 (14:24239265 A>G), RS1005406544 (14:24242744 G>C,T), RS1006031928 (14:24242297 T>C), RS1006657634 (14:24243288 A>T), RS1006779352 (14:24243385 A>AC), RS1006936304 (14:24243054 A>C,G), RS1007253878 (14:24241569 A>T), RS1007505474 (14:24243146 C>T), RS1009873083 (14:24239619 C>A,G,T)

Disease associations

OMIM: gene MIM:604319 | disease phenotypes: MIM:127550, MIM:613990, MIM:268130, MIM:609135, MIM:614742

GenCC curated gene-disease

Disease	Classification	Inheritance
dyskeratosis congenita, autosomal dominant 3	Definitive	Autosomal dominant
Revesz syndrome	Definitive	Autosomal dominant
pulmonary fibrosis	Moderate	Autosomal dominant
dyskeratosis congenita	Supportive	Autosomal dominant
Hoyeraal-Hreidarsson syndrome	Supportive	Autosomal dominant
thyroid gland papillary carcinoma	Limited	Autosomal dominant

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
dyskeratosis congenita, autosomal dominant 3	Definitive	AD

Mondo (10): dyskeratosis congenita (MONDO:0015780), dyskeratosis congenita, autosomal dominant 3 (MONDO:0013522), Revesz syndrome (MONDO:0009990), dyskeratosis congenita, autosomal dominant 1 (MONDO:0007485), pulmonary fibrosis (MONDO:0002771), Hoyeraal-Hreidarsson syndrome (MONDO:0018045), breast cancer (MONDO:0007254), aplastic anemia (MONDO:0015909), pulmonary fibrosis and/or bone marrow failure, Telomere-related, 1 (MONDO:0013878), thyroid gland papillary carcinoma (MONDO:0005075)

Orphanet (5): Dyskeratosis congenita (Orphanet:1775), Revesz syndrome (Orphanet:3088), Hoyeraal-Hreidarsson syndrome (Orphanet:3322), Rare aplastic anemia (Orphanet:182040), Idiopathic aplastic anemia (Orphanet:88)

HPO phenotypes

134 total (30 of 134 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000008	Abnormal morphology of female internal genitalia
HP:0000028	Cryptorchidism
HP:0000035	Abnormal testis morphology
HP:0000164	Abnormality of the dentition
HP:0000252	Microcephaly
HP:0000327	Hypoplasia of the maxilla
HP:0000365	Hearing impairment
HP:0000485	Megalocornea
HP:0000498	Blepharitis
HP:0000499	Abnormal eyelash morphology
HP:0000518	Cataract
HP:0000534	Abnormal eyebrow morphology
HP:0000541	Retinal detachment
HP:0000555	Leukocoria
HP:0000572	Visual loss
HP:0000600	Abnormality of the pharynx
HP:0000639	Nystagmus
HP:0000668	Hypodontia
HP:0000670	Carious teeth
HP:0000679	Taurodontia
HP:0000704	Periodontitis
HP:0000750	Delayed speech and language development
HP:0000819	Diabetes mellitus
HP:0000938	Osteopenia
HP:0000939	Osteoporosis
HP:0000958	Dry skin
HP:0000975	Hyperhidrosis
HP:0000982	Palmoplantar keratoderma
HP:0001034	Hypermelanotic macule

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST005991_21	Platelet count	6.000000e-15
GCST008366_1	Leukocyte telomere length	2.000000e-42

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004309	platelet count

MeSH disease descriptors (6)

Descriptor	Name	Tree numbers
D000741	Anemia, Aplastic	C15.378.050.085; C15.378.190.223.250
D019871	Dyskeratosis Congenita	C15.378.190.223.500.750; C16.131.831.150; C16.320.322.108; C16.320.850.235; C17.800.804.150; C17.800.827.235
D011658	Pulmonary Fibrosis	C08.381.483.652; C23.550.355.644
C565079	Dyskeratosis Congenita, Autosomal Dominant (supp.)
C536068	Hoyeraal Hreidarsson syndrome (supp.)
C538371	Revesz Debuse syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

47 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, increases abundance, increases expression	3
Air Pollutants	increases expression, affects expression, affects cotreatment, increases abundance	2
Cisplatin	affects expression, increases expression	2
Ozone	affects cotreatment, increases expression, increases abundance, affects expression	2
Valproic Acid	affects expression, decreases expression	2
aristolochic acid I	decreases expression	1
GSK-J4	decreases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, increases expression, increases abundance	1
bisphenol A	decreases expression	1
beta-lapachone	increases expression	1
pyrrolidine dithiocarbamic acid	decreases expression	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
methacrylaldehyde	affects cotreatment, increases expression, increases abundance	1
isobutyl alcohol	affects cotreatment, decreases expression, increases abundance	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
mithramycin A	affects binding, decreases reaction, increases expression	1
perfluorooctane sulfonic acid	increases expression	1
3-(4-methylphenylsulfonyl)-2-propenenitrile	decreases expression	1
ICG 001	increases expression	1
abrine	increases expression	1
jinfukang	increases expression	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	increases expression	1
Bortezomib	decreases expression, decreases reaction	1
Resveratrol	decreases expression	1
Temozolomide	decreases expression	1
Decitabine	affects expression	1
Troglitazone	increases expression	1
Acrolein	affects cotreatment, increases expression, increases abundance	1
Arsenic	increases abundance, decreases expression	1

Clinical trials (associated diseases)

379 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT04619680	PHASE4	COMPLETED	The Study of the Use of Nintedanib in Slowing Lung Disease in Patients With Fibrotic or Non-Fibrotic Interstitial Lung Disease Related to COVID-19
NCT07570888	PHASE4	NOT_YET_RECRUITING	This is a Trial Designed to Evaluate the Combination of Nerandomilast With Mycophenolate Across a Wide Variety of Pulmonary Fibrosis Subtypes, With the Aim of Providing Clinicians With Assurance That This is an Appropriate Therapeutic Combination.
NCT07354698	PHASE4	NOT_YET_RECRUITING	Application of Mitoxantrone Hydrochloride Injection in Transoral Robotic Thyroid Cancer Surgery
NCT00014638	PHASE4	COMPLETED	Letrozole in Treating Postmenopausal Women With Metastatic Breast Cancer
NCT00022386	PHASE4	COMPLETED	Epoetin Alfa in Treating Chemotherapy-Related Anemia in Women With Stage I, Stage II, or Stage III Breast Cancer
NCT00029224	PHASE4	COMPLETED	Treatment With Zoledronic Acid in Patients With Breast Cancer, Multiple Myeloma, and Prostate Cancer With Cancer Related Bone Lesions
NCT00030758	PHASE4	UNKNOWN	Filgrastim or Pegfilgrastim in Preventing Neutropenia in Women Receiving Chemotherapy Following Surgery for Breast Cancer
NCT00082277	PHASE4	COMPLETED	Anastrozole Biphosphonate Study in Postmenopausal Women With Hormone-Receptor-Positive Early Breast Cancer
NCT00087620	PHASE4	TERMINATED	A Study of Capecitabine In Combination With Docetaxel vs Capecitabine Followed by Docetaxel As First-Line Treatment For Metastatic Breast Cancer
NCT00121836	PHASE4	COMPLETED	A Study of Xeloda (Capecitabine) in Women With HER2-Negative Metastatic Breast Cancer
NCT00126360	PHASE4	UNKNOWN	STARS Breast Trial (Study of Anastrozole and Radiotherapy Sequencing Pilot)
NCT00127933	PHASE4	COMPLETED	XeNA Study - A Study of Xeloda (Capecitabine) in Patients With Invasive Breast Cancer
NCT00128297	PHASE4	COMPLETED	Pamidronate Administration in Breast Cancer Patients With Bone Metastases
NCT00129597	PHASE4	UNKNOWN	Effect of Ketalar to Prevent Postoperative Chronic Pain After Mastectomy
NCT00131170	PHASE4	COMPLETED	Paravertebral Block for Breast Surgery
NCT00156039	PHASE4	COMPLETED	Randomized Trial of Follow-up Strategies in Breast Cancer
NCT00160901	PHASE4	COMPLETED	Complementary Therapies for the Reduction of Side Effects During Chemotherapy for Breast Cancer
NCT00171847	PHASE4	TERMINATED	Study of the Efficacy and Safety of Letrozole Combined With Trastuzumab in Patients With Metastatic Breast Cancer
NCT00176046	PHASE4	COMPLETED	Mistletoe Extract in Early or Advanced Breast Cancer, A Feasibility Study
NCT00190697	PHASE4	COMPLETED	A Study of LY353381 (Arzoxifene) for Patients Who Benefitted From This Drug in Other Oncology Trials and Wished to Continue Treatment
NCT00234195	PHASE4	COMPLETED	Wellbutrin XL, Major Depressive Disorder and Breast Cancer
NCT00237133	PHASE4	COMPLETED	Treatment of Locally Advanced Breast Cancer With Letrozole in Postmenopausal Women
NCT00237224	PHASE4	COMPLETED	Open Label Study of Postmenopausal Women With ER and /or PgR Positive Breast Cancer Treated With Letrozole
NCT00241046	PHASE4	TERMINATED	Letrozole in the Treatment of 1st and 2nd Line Hormone Receptor Positive Breast Cancer: Pre-therapeutic Risk Assessment
NCT00277160	PHASE4	COMPLETED	A Study of Primary Prophylaxis With Neulasta (Pegfilgrastim) Versus Secondary Prophylaxis After Chemotherapy in Elderly Subjects (>/= 65 Years Old) With Cancer
NCT00323479	PHASE4	COMPLETED	Arthralgia During Anastrozole Therapy for Breast Cancer
NCT00334139	PHASE4	COMPLETED	Effect of Zoledronic Acid on Bone Metabolism in Patients With Bone Metastasis and Prostate or Breast Cancer
NCT00356148	PHASE4	COMPLETED	The Efficacy of Prophylactic Antibiotic Administration During Breast Cancer Surgery in Overweight Patients.
NCT00372476	PHASE4	COMPLETED	Efficacy and Safety of Imatinib and Vinorelbine in Patients With Advanced Breast Cancer
NCT00413491	PHASE4	UNKNOWN	National Screening in Denmark With MR Versus Mammography and Ultrasound of Women With BRCA1 or BRCA2 Mutations
NCT00484614	PHASE4	UNKNOWN	Study the Role of Positron Emission Mammography in Pre-surgical Planning for Breast Cancer
NCT00485953	PHASE4	COMPLETED	Effect of Bisphosphonate on Bone Loss in Postmenopausal Women With Breast Cancer Initiating Aromatase Inhibitor Therapy
NCT00496678	PHASE4	COMPLETED	Trial of Patient Navigation-Activation
NCT00531973	PHASE4	UNKNOWN	A Study of Liposomal Doxorubicin in Women With Breast Cancer Exploiting Tissue Doppler Imaging
NCT00537771	PHASE4	COMPLETED	Liver Safety Under Upfront Arimidex vs Tamoxifen
NCT00544986	PHASE4	COMPLETED	A Prospective,Open-label Study of Anastrozole in Post-menopausal Women With Hormone Sensitive Advanced Breast Cancer
NCT00613275	PHASE4	COMPLETED	Patient Navigation in the Safety Net:CONNECTeDD
NCT00638599	PHASE4	COMPLETED	Comparison of Laryngeal Mask Airway (LMA®) and Tracheal Tube in Modified Radical Mastectomy on Breast Cancer
NCT00647075	PHASE4	UNKNOWN	Yunzhi as Dietary Supplement in Breast Cancer
NCT00688909	PHASE4	COMPLETED	Rheumatological Evaluation of Anastrozole and Letrozole as Adjuvant Treatment in Post-menopausal Women With Breast Cancer