RINT1

Summary

RINT1 (RAD50 interactor 1, HGNC:21876) is a protein-coding gene on chromosome 7q22.3, encoding RAD50-interacting protein 1 (Q6NUQ1). Involved in regulation of membrane traffic between the Golgi and the endoplasmic reticulum (ER); the function is proposed to depend on its association in the NRZ complex which is believed to play a role in SNARE assembly at the ER. It is a selective cancer dependency (DepMap: 87.8% of cell lines).

This gene encodes a protein first identified for its ability to interact with the RAD50 double strand break repair protein, with the resulting interaction implicated in the regulation of cell cycle progression and telomere length. The encoded protein may also play a role in trafficking of cellular cargo from the endosome to the trans-Golgi network. Mutations in this gene may be associated with breast cancer in human patients.

Source: NCBI Gene 60561 — RefSeq curated summary.

At a glance

• Gene–disease (curated): infantile liver failure syndrome 3 (Strong, GenCC) — +5 more curated relationships
• Clinical variants (ClinVar): 1,441 total — 28 pathogenic, 16 likely-pathogenic
• Phenotypes (HPO): 21
• Cancer dependency (DepMap): dependent in 87.8% of screened cell lines
• Dosage sensitivity (ClinGen): haploinsufficiency no evidence, triplosensitivity no evidence
• MANE Select transcript: NM_021930

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:21876
Approved symbol	RINT1
Name	RAD50 interactor 1
Location	7q22.3
Locus type	gene with protein product
Status	Approved
Aliases	FLJ11785, RINT-1
Ensembl gene	ENSG00000135249
Ensembl biotype	protein_coding
OMIM	610089
Entrez	60561

Gene structure

Transcript identifiers

Ensembl transcripts: 21 — 15 protein_coding, 3 nonsense_mediated_decay, 2 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000257700, ENST00000467392, ENST00000474123, ENST00000477285, ENST00000482041, ENST00000493041, ENST00000493258, ENST00000497979, ENST00000899070, ENST00000899071, ENST00000899072, ENST00000899073, ENST00000899074, ENST00000930232, ENST00000930233, ENST00000930234, ENST00000930235, ENST00000930236, ENST00000930237, ENST00000967558, ENST00000967559

RefSeq mRNA: 5 — MANE Select: NM_021930 NM_001346599, NM_001346600, NM_001346601, NM_001346603, NM_021930

CCDS: CCDS34726

Canonical transcript exons

ENST00000257700 — 15 exons

Exon	Start	End
ENSE00001025424	105532824	105532869
ENSE00001132619	105567119	105567677
ENSE00001132624	105532201	105532357
ENSE00003472389	105550055	105550165
ENSE00003512093	105542408	105542649
ENSE00003516372	105551570	105551707
ENSE00003519373	105555028	105555227
ENSE00003547251	105563733	105563947
ENSE00003559160	105548554	105548710
ENSE00003567912	105536565	105536749
ENSE00003590548	105565530	105565648
ENSE00003621560	105550261	105550486
ENSE00003638507	105546910	105547083
ENSE00003646246	105547184	105547333
ENSE00003650105	105565277	105565457

Expression profiles

Bgee: expression breadth ubiquitous, 259 present calls, max score 90.84.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 31.0130 / max 191.1711, expressed in 1816 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
80340	27.6532	1815
80341	2.5512	1226
80342	0.3927	177
80338	0.3725	96
80339	0.0435	8

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
tibia	UBERON:0000979	90.84	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	89.35	gold quality
body of pancreas	UBERON:0001150	88.69	gold quality
hindlimb stylopod muscle	UBERON:0004252	88.01	gold quality
gastrocnemius	UBERON:0001388	87.49	gold quality
muscle of leg	UBERON:0001383	87.21	gold quality
right uterine tube	UBERON:0001302	87.19	gold quality
esophagus squamous epithelium	UBERON:0006920	87.02	gold quality
calcaneal tendon	UBERON:0003701	86.31	gold quality
skin of abdomen	UBERON:0001416	86.26	gold quality
skin of leg	UBERON:0001511	86.25	gold quality
cerebellar hemisphere	UBERON:0002245	86.21	gold quality
mucosa of stomach	UBERON:0001199	86.06	gold quality
cerebellar cortex	UBERON:0002129	86.01	gold quality
sural nerve	UBERON:0015488	85.96	gold quality
right hemisphere of cerebellum	UBERON:0014890	85.87	gold quality
biceps brachii	UBERON:0001507	85.77	gold quality
ganglionic eminence	UBERON:0004023	85.75	gold quality
stromal cell of endometrium	CL:0002255	85.66	gold quality
cortical plate	UBERON:0005343	85.56	gold quality
pancreas	UBERON:0001264	85.47	gold quality
lower esophagus mucosa	UBERON:0035834	85.44	gold quality
adenohypophysis	UBERON:0002196	85.27	gold quality
esophagus mucosa	UBERON:0002469	85.14	gold quality
secondary oocyte	CL:0000655	85.12	gold quality
tibial nerve	UBERON:0001323	85.03	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	85.01	gold quality
ectocervix	UBERON:0012249	84.72	gold quality
zone of skin	UBERON:0000014	84.62	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	84.60	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.38

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

29 targeting RINT1, 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-1252-5P	100.00	69.80	2774
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-3605-5P	99.96	67.12	932
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548T-3P	99.96	70.64	3753
HSA-MIR-145-5P	99.92	71.13	1836
HSA-MIR-5195-3P	99.92	70.92	1877
HSA-MIR-3121-3P	99.82	71.96	3630
HSA-MIR-4446-5P	99.72	69.19	2544
HSA-MIR-4755-5P	99.71	70.34	2716
HSA-MIR-5006-3P	99.71	70.26	2728
HSA-MIR-12124	99.68	69.17	2700
HSA-MIR-7157-5P	99.66	69.33	1829
HSA-MIR-4310	99.59	68.84	2527
HSA-MIR-4652-3P	99.33	70.02	2742
HSA-MIR-122B-3P	99.21	68.90	1333
HSA-MIR-21-3P	99.21	68.95	1312
HSA-MIR-892C-5P	99.16	70.56	2116
HSA-MIR-421	98.90	67.04	1883
HSA-MIR-487A-5P	98.85	69.37	993
HSA-MIR-487B-5P	98.85	69.48	987
HSA-MIR-605-5P	98.79	68.24	1161
HSA-MIR-6728-3P	98.63	67.63	1534
HSA-MIR-676-5P	98.49	68.87	1492
HSA-MIR-6881-3P	98.04	68.24	1777
HSA-MIR-585-5P	97.54	69.02	955
HSA-MIR-512-5P	97.47	66.48	591
HSA-MIR-3914	94.91	65.77	643

Functional genomics

ClinGen dosage: haploinsufficiency 0 (no evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map DepMap (CRISPR cell-line fitness): dependent in 87.8% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 14)

• RINT-1 coordinates the localization and function of ZW10 by serving as a link between ZW10 and the SNARE complex comprising syntaxin 18. (PMID:16571679)
• These findings suggest that RINT-1 serves as a novel tumor suppressor essential for maintaining the dynamic integrity of the Golgi apparatus and the centrosome, a prerequisite to their proper coordination during cell division. (PMID:17470549)
• Rab6 regulates distinct Golgi trafficking pathways involving two separate protein complexes: ZW10/RINT-1 and COG. (PMID:17699596)
• Results together suggest that NAG links between p31 and ZW10-RINT-1 and is involved in Golgi-to-ER transport. (PMID:19369418)
• RINT1 was validated as a novel glioblastoma oncogene (PMID:23074196)
• RINT-1 is also required for endosome-to-trans-Golgi network trafficking. (PMID:23885118)
• Results identified RINT1 as a putative breast cancer predisposition gene that also seems to be associated with risk for a spectrum of other cancers similar to those that have previously been described for Lynch syndrome. (PMID:25050558)
• Results suggest that high RAD50 interactor 1 (RINT1) expression may represent a risk factor for low-grade gliomas (LGGs)-related seizures. (PMID:25304616)
• RINT-1 interacts with MSP58 and UBF within nucleoli and plays a role in ribosomal gene transcription. (PMID:27530925)
• Study presents evidence that in the Caucasian population, RINT1 does not represent a moderate- penetrance breast cancer susceptibility gene, and find no evidence to support an association of RINT1 mutation with Lynch syndrome-related cancer incidence in breast cancer families. (PMID:27544226)
• HPV E2 protein targets Rad50-interacting protein 1 (Rint1) to facilitate virus genome replication. (PMID:28031358)
• these data are more consistent with the hypothesis that RINT1 functions as an oncogene rather than a tumor suppressor gene in the context of colorectal cancer. (PMID:28264000)
• RINT1 Bi-allelic Variations Cause Infantile-Onset Recurrent Acute Liver Failure and Skeletal Abnormalities. (PMID:31204009)
• RINT1 Regulates SUMOylation and the DNA Damage Response to Preserve Cellular Homeostasis in Pancreatic Cancer. (PMID:33531371)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	rint1	ENSDARG00000005547
mus_musculus	Rint1	ENSMUSG00000028999
rattus_norvegicus	Rint1	ENSRNOG00000022182
drosophila_melanogaster	Rint1	FBGN0035762

Protein

Protein identifiers

RAD50-interacting protein 1 — Q6NUQ1 (reviewed: Q6NUQ1)

Alternative names: RAD50 interactor 1

All UniProt accessions (5): C9J5S3, Q6NUQ1, F8WAZ2, F8WC46, F8WDC5

UniProt curated annotations — full annotation on UniProt →

Function. Involved in regulation of membrane traffic between the Golgi and the endoplasmic reticulum (ER); the function is proposed to depend on its association in the NRZ complex which is believed to play a role in SNARE assembly at the ER. May play a role in cell cycle checkpoint control. Essential for telomere length control.

Subunit / interactions. Component of the NRZ complex composed of NBAS, ZW10 and RINT1/TIP20L; NRZ associates with SNAREs STX18, USE1L, BNIP1/SEC20L and SEC22B (the assembly has been described as syntaxin 18 complex). Interacts directly with BNIP1/SEC20L and ZW10. Interacts with UVRAG. Interacts with RAD50 during late S and G2/M phases. Interacts with RBL2, preferentially with the active, hypophosphorylated form.

Subcellular location. Cytoplasm. Endoplasmic reticulum membrane.

Disease relevance. Infantile liver failure syndrome 3 (ILFS3) [MIM:618641] A form of infantile liver failure syndrome, a life-threatening disorder of hepatic function that manifests with acute liver failure in the first months or years of life. ILFS3 is an autosomal recessive form characterized by recurrent episodes of acute liver failure often triggered by infection or fever. Affected individuals also have skeletal anomalies of the vertebral bodies and femoral heads. The disease is caused by variants affecting the gene represented in this entry.

Miscellaneous. According to PubMed:11096100, a longer form, which may be due to the differential initiation of translation using a non-AUG codon, may exist. However, the existence of such form has not been clearly demonstrated.

Similarity. Belongs to the RINT1 family.

RefSeq proteins (5): NP_001333528, NP_001333529, NP_001333530, NP_001333532, NP_068749* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR007528	RINT1_Tip20	Family
IPR042044	EXOC6PINT-1/Sec15/Tip20_C_dom2	Homologous_superfamily

Pfam: PF04437

UniProt features (12 total): sequence variant 6, sequence conflict 2, chain 1, domain 1, region of interest 1, coiled-coil region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q6NUQ1-F1	85.97	0.63

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-6811434	COPI-dependent Golgi-to-ER retrograde traffic

MSigDB gene sets: 203 (showing top): GOBP_CELL_CYCLE_PHASE_TRANSITION, GOBP_VESICLE_MEDIATED_TRANSPORT, REACTOME_MEMBRANE_TRAFFICKING, GOBP_MITOTIC_G2_M_TRANSITION_CHECKPOINT, GOBP_REGULATION_OF_VESICLE_MEDIATED_TRANSPORT, GOBP_REGULATION_OF_CELL_CYCLE_G2_M_PHASE_TRANSITION, GOBP_ENDOPLASMIC_RETICULUM_TO_GOLGI_VESICLE_MEDIATED_TRANSPORT, GOBP_NEGATIVE_REGULATION_OF_CELL_CYCLE_PROCESS, KESHELAVA_MULTIPLE_DRUG_RESISTANCE, GOBP_NEGATIVE_REGULATION_OF_CELL_CYCLE, GOBP_REGULATION_OF_CELLULAR_LOCALIZATION, GOBP_REGULATION_OF_CELL_CYCLE, GOBP_MITOTIC_G2_DNA_DAMAGE_CHECKPOINT_SIGNALING, GOBP_NEGATIVE_REGULATION_OF_MITOTIC_CELL_CYCLE, GOBP_DNA_DAMAGE_RESPONSE

GO Biological Process (6): endoplasmic reticulum to Golgi vesicle-mediated transport (GO:0006888), retrograde vesicle-mediated transport, Golgi to endoplasmic reticulum (GO:0006890), mitotic G2 DNA damage checkpoint signaling (GO:0007095), protein transport (GO:0015031), regulation of ER to Golgi vesicle-mediated transport (GO:0060628), vesicle-mediated transport (GO:0016192)

GO Molecular Function (1): protein binding (GO:0005515)

GO Cellular Component (6): endoplasmic reticulum (GO:0005783), endoplasmic reticulum membrane (GO:0005789), cytosol (GO:0005829), Dsl1/NZR complex (GO:0070939), cytoplasm (GO:0005737), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Golgi-to-ER retrograde transport	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cytoplasm	3
cellular anatomical structure	3
Golgi vesicle transport	2
transport	2
intercellular transport	1
intracellular transport	1
mitotic G2 phase	1
mitotic DNA damage checkpoint signaling	1
mitotic G2/M transition checkpoint	1
intracellular protein localization	1
establishment of protein localization	1
endoplasmic reticulum to Golgi vesicle-mediated transport	1
regulation of intracellular transport	1
regulation of vesicle-mediated transport	1
cellular process	1
binding	1
endomembrane system	1
intracellular membrane-bounded organelle	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
vesicle tethering complex	1
endoplasmic reticulum protein-containing complex	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

1576 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RINT1	ZW10	O43264	997
RINT1	RAB18	Q9NP72	931
RINT1	BNIP1	Q12981	851
RINT1	STX18	Q9P2W9	839
RINT1	ZWILCH	Q9H900	837
RINT1	ZNF787	Q6DD87	819
RINT1	COG1	Q8WTW3	795
RINT1	RBL2	Q08999	774
RINT1	SCFD1	Q8WVM8	726
RINT1	USE1	Q9NZ43	689
RINT1	RAD50	Q92878	663
RINT1	COG3	Q96JB2	647
RINT1	VPS53	Q5VIR6	603
RINT1	NBAS	A2RRP1	593
RINT1	UVRAG	Q9P2Y5	577

IntAct

497 interactions, top by confidence:

A	B	Type	Score
RINT1	ZW10	psi-mi:“MI:0915”(physical association)	0.890
RINT1	NBAS	psi-mi:“MI:0914”(association)	0.830
STX18	NBAS	psi-mi:“MI:0914”(association)	0.810
SNW1	RINT1	psi-mi:“MI:0915”(physical association)	0.780
RINT1	RIBC1	psi-mi:“MI:0915”(physical association)	0.780
RINT1	SGF29	psi-mi:“MI:0915”(physical association)	0.780
RINT1	SNW1	psi-mi:“MI:0915”(physical association)	0.780
RIBC1	RINT1	psi-mi:“MI:0915”(physical association)	0.780
SGF29	RINT1	psi-mi:“MI:0915”(physical association)	0.780
RINT1	CWF19L2	psi-mi:“MI:0915”(physical association)	0.720
TXLNA	RINT1	psi-mi:“MI:0915”(physical association)	0.720
RBM41	RINT1	psi-mi:“MI:0915”(physical association)	0.720
FAM110A	RINT1	psi-mi:“MI:0915”(physical association)	0.720
RINT1	SH2D4A	psi-mi:“MI:0915”(physical association)	0.720
RINT1	AIRIM	psi-mi:“MI:0915”(physical association)	0.720
CWF19L2	RINT1	psi-mi:“MI:0915”(physical association)	0.720
RINT1	RBM41	psi-mi:“MI:0915”(physical association)	0.720

BioGRID (325): RINT1 (Two-hybrid), RINT1 (Two-hybrid), RINT1 (Two-hybrid), RINT1 (Two-hybrid), RINT1 (Two-hybrid), RINT1 (Two-hybrid), RINT1 (Two-hybrid), RINT1 (Two-hybrid), RINT1 (Two-hybrid), RINT1 (Two-hybrid), RINT1 (Two-hybrid), RINT1 (Two-hybrid), RINT1 (Two-hybrid), SH2D4A (Two-hybrid), RSRC2 (Two-hybrid)

ESM2 similar proteins: A2VDR8, A4IF89, B1AY13, B1WC10, F4HQ84, F4I4B6, F4JHH5, O00471, O15068, O54921, O54924, P0CI65, P83436, P97878, Q14746, Q2TBH9, Q3T1G7, Q3TPX4, Q3UM29, Q5U247, Q5ZJ43, Q62717, Q6DK84, Q6GLR7, Q6NMI3, Q6NUQ1, Q6PGF7, Q7TNH6, Q7Z494, Q80TJ1, Q86UW7, Q8BYR5, Q8BZ36, Q8C0L8, Q8C456, Q8CI04, Q8IYI6, Q8L838, Q8WTW3, Q921L5

Diamond homologs: Q6NUQ1, Q8BZ36, Q9VS46

SIGNOR signaling

4 interactions.

A	Effect	B	Mechanism
UVRAG	“up-regulates activity”	RINT1	binding
RAD50	“up-regulates activity”	RINT1	binding
RINT1	down-regulates	Telomere_maintenance
RINT1	“form complex”	“NRZ complex”	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 69 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
COPI-dependent Golgi-to-ER retrograde traffic	5	13.2×	1e-02

GO biological processes:

GO term	Partners	Fold	FDR
retrograde vesicle-mediated transport, Golgi to endoplasmic reticulum	5	30.6×	2e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

1441 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	28
Likely pathogenic	16
Uncertain significance	896
Likely benign	422
Benign	15

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1000452	NC_000007.13:g.(?105187351)(105192160_?)del	Pathogenic
1005692	NM_021930.6(RINT1):c.1782_1789del (p.Asp594fs)	Pathogenic
1036148	NM_021930.6(RINT1):c.165T>G (p.Tyr55Ter)	Pathogenic
1054026	NM_021930.6(RINT1):c.373dup (p.Thr125fs)	Pathogenic
1371417	NM_021930.6(RINT1):c.1726_1727del (p.Leu576fs)	Pathogenic
1376273	NC_000007.13:g.(?105182845)(105183106_?)del	Pathogenic
1448493	NC_000007.13:g.(?105190492)(105192164_?)del	Pathogenic
2037932	NM_021930.6(RINT1):c.1510C>T (p.Gln504Ter)	Pathogenic
2061915	NM_021930.6(RINT1):c.796del (p.Tyr266fs)	Pathogenic
2500162	NM_021930.6(RINT1):c.1672-1G>A	Pathogenic
2702379	NM_021930.6(RINT1):c.338C>G (p.Ser113Ter)	Pathogenic
2726355	NM_021930.6(RINT1):c.1519G>T (p.Glu507Ter)	Pathogenic
2726444	NM_021930.6(RINT1):c.1066C>T (p.Gln356Ter)	Pathogenic
2768202	NM_021930.6(RINT1):c.326del (p.Asn109fs)	Pathogenic
2828230	NM_021930.6(RINT1):c.105del (p.Val36fs)	Pathogenic
2842593	NM_021930.6(RINT1):c.1296_1297del (p.Glu432fs)	Pathogenic
2842906	NM_021930.6(RINT1):c.643del (p.Ala215fs)	Pathogenic
3245925	NC_000007.13:g.(?105172763)(105189167_?)del	Pathogenic
3245926	NC_000007.13:g.(?105176992)(105183116_?)del	Pathogenic
410783	NM_021930.6(RINT1):c.1348dup (p.Met450fs)	Pathogenic
4720922	NM_021930.6(RINT1):c.839C>A (p.Ser280Ter)	Pathogenic
4720990	NM_021930.6(RINT1):c.1111G>T (p.Glu371Ter)	Pathogenic
599396	NM_021930.6(RINT1):c.1109T>C (p.Leu370Pro)	Pathogenic
642915	NM_021930.6(RINT1):c.1849G>T (p.Glu617Ter)	Pathogenic
646401	NC_000007.14:g.(?105542398)(105551717_?)del	Pathogenic
661731	NC_000007.14:g.(?105532306)(105536759_?)del	Pathogenic
692227	NM_021930.6(RINT1):c.1333+1G>T	Pathogenic
968069	NM_021930.6(RINT1):c.896_915dup (p.Ile306fs)	Pathogenic
1021026	NM_021930.6(RINT1):c.690-1G>A	Likely pathogenic
1023836	NC_000007.13:g.(?105173265)(105187786_?)dup	Likely pathogenic

SpliceAI

2695 predictions. Top by Δscore:

Variant	Effect	Δscore
7:105532356:CGG:C	donor_loss	1.0000
7:105532358:GTGAG:G	donor_loss	1.0000
7:105532822:A:AG	acceptor_gain	1.0000
7:105532823:G:GG	acceptor_gain	1.0000
7:105532865:GAAAA:G	donor_gain	1.0000
7:105532870:G:GG	donor_gain	1.0000
7:105536559:TTGTA:T	acceptor_loss	1.0000
7:105536560:TGTA:T	acceptor_loss	1.0000
7:105536562:TAG:T	acceptor_loss	1.0000
7:105536563:A:AG	acceptor_gain	1.0000
7:105536564:G:GG	acceptor_gain	1.0000
7:105536750:GT:G	donor_loss	1.0000
7:105536751:T:A	donor_loss	1.0000
7:105542394:A:AG	acceptor_gain	1.0000
7:105542395:A:G	acceptor_gain	1.0000
7:105542646:TAAG:T	donor_loss	1.0000
7:105542647:AAGGT:A	donor_loss	1.0000
7:105542648:AGGTA:A	donor_loss	1.0000
7:105542649:GGTAA:G	donor_loss	1.0000
7:105542650:GTAAA:G	donor_loss	1.0000
7:105542651:T:A	donor_loss	1.0000
7:105543434:G:GT	donor_gain	1.0000
7:105546908:A:AG	acceptor_gain	1.0000
7:105546908:AGT:A	acceptor_gain	1.0000
7:105546909:G:GG	acceptor_gain	1.0000
7:105546909:GT:G	acceptor_gain	1.0000
7:105546909:GTG:G	acceptor_gain	1.0000
7:105547252:GCT:G	donor_gain	1.0000
7:105547289:T:G	donor_gain	1.0000
7:105550049:CCTTA:C	acceptor_loss	1.0000

AlphaMissense

5230 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
7:105550465:T:A	W438R	1.000
7:105550465:T:C	W438R	1.000
7:105547215:T:A	W241R	0.999
7:105547215:T:C	W241R	0.999
7:105548672:C:G	H320D	0.999
7:105548675:T:C	F321L	0.999
7:105548677:C:A	F321L	0.999
7:105548677:C:G	F321L	0.999
7:105551573:C:A	A446D	0.999
7:105551614:T:A	W460R	0.999
7:105551614:T:C	W460R	0.999
7:105551690:T:C	L485P	0.999
7:105565278:T:A	W630R	0.999
7:105565278:T:C	W630R	0.999
7:105565573:T:C	L704P	0.999
7:105547052:T:A	W220R	0.998
7:105547052:T:C	W220R	0.998
7:105548676:T:C	F321S	0.998
7:105550061:T:A	W335R	0.998
7:105550061:T:C	W335R	0.998
7:105550085:T:A	W343R	0.998
7:105550085:T:C	W343R	0.998
7:105555031:G:T	R492M	0.998
7:105555070:T:C	F505S	0.998
7:105555112:G:C	R519P	0.998
7:105555180:G:C	A542P	0.998
7:105555205:T:C	L550P	0.998
7:105563746:T:C	L562P	0.998
7:105567129:G:C	A733P	0.998
7:105547049:T:C	F219L	0.997

dbSNP variants (sampled 300 via entrez): RS1000116941 (7:105532420 C>A,T), RS1000263603 (7:105558388 C>T), RS1000353574 (7:105538554 G>A,T), RS1000414662 (7:105544062 T>C), RS1000460642 (7:105550252 T>G), RS1000514641 (7:105543375 C>G,T), RS1000546026 (7:105563415 C>T), RS1000586843 (7:105543873 G>A), RS1000635941 (7:105532170 G>A,T), RS1000686528 (7:105537264 G>A), RS1000747346 (7:105537826 C>T), RS1000748029 (7:105549818 T>G), RS1000800066 (7:105542905 A>C,G), RS1000852507 (7:105550609 T>A), RS1000865911 (7:105531957 G>T)

Disease associations

OMIM: gene MIM:610089 | disease phenotypes: MIM:618641, MIM:188550

GenCC curated gene-disease

Disease	Classification	Inheritance
infantile liver failure syndrome 3	Strong	Autosomal recessive
hereditary spastic paraplegia	Strong	Autosomal recessive
infantile liver failure syndrome 2	Supportive	Autosomal recessive
breast cancer	Disputed Evidence	Autosomal dominant
familial ovarian cancer	No Known Disease Relationship	Unknown

ClinGen Gene-Disease Validity (2)

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

Disease	Classification	Inheritance
hereditary breast carcinoma	Refuted	AD
familial ovarian cancer	No Known Disease Relationship	AD

Mondo (8): infantile liver failure syndrome 3 (MONDO:0032844), hereditary neoplastic syndrome (MONDO:0015356), familial ovarian cancer (MONDO:0016248), thyroid cancer, nonmedullary, 1 (MONDO:0008567), hereditary breast ovarian cancer syndrome (MONDO:0003582), breast cancer (MONDO:0007254), infantile liver failure syndrome 2 (MONDO:0014659), hereditary spastic paraplegia (MONDO:0019064)

Orphanet (3): Inherited cancer-predisposing syndrome (Orphanet:140162), Hereditary breast and/or ovarian cancer syndrome (Orphanet:145), OBSOLETE: Familial ovarian cancer (Orphanet:213517)

HPO phenotypes

21 total (21 of 21 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000926	Platyspondyly
HP:0000952	Jaundice
HP:0001396	Cholestasis
HP:0001397	Hepatic steatosis
HP:0001744	Splenomegaly
HP:0001762	Talipes equinovarus
HP:0001987	Hyperammonemia
HP:0002240	Hepatomegaly
HP:0002480	Hepatic encephalopathy
HP:0002910	Elevated circulating hepatic transaminase concentration
HP:0003170	Abnormal acetabulum morphology
HP:0003593	Infantile onset
HP:0003819	Death in childhood
HP:0004322	Short stature
HP:0004568	Beaking of vertebral bodies
HP:0006554	Acute hepatic failure
HP:0008151	Prolonged prothrombin time
HP:0008479	Hypoplastic vertebral bodies
HP:0010574	Abnormality of the epiphysis of the femoral head
HP:0012852	Hepatic bridging fibrosis

GWAS associations

0 associations (top):

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D061325	Hereditary Breast and Ovarian Cancer Syndrome	C04.588.180.483; C04.588.322.455.431; C04.700.517; C12.050.351.500.056.630.705.431; C12.050.351.937.418.685.431; C12.100.250.056.630.705.431; C12.900.418.685.431; C16.320.700.517; C17.800.090.500.483; C19.344.410.431; C19.391.630.705.431
D009386	Neoplastic Syndromes, Hereditary	C04.700; C16.320.700
D015419	Spastic Paraplegia, Hereditary	C10.500.300.820; C10.574.500.495.820; C10.668.829.800.300.820; C16.131.666.300.820; C16.320.400.375.820

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

23 total (human), top 23 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Air Pollutants	increases abundance, decreases expression, increases expression, affects expression	4
Arsenic	affects methylation, affects cotreatment, increases abundance, increases expression	2
Smoke	decreases expression, increases abundance	2
Tretinoin	affects expression, decreases expression	2
Particulate Matter	decreases expression, increases abundance, increases expression	2
dicrotophos	decreases expression	1
sodium arsenite	affects cotreatment, increases abundance, increases expression	1
manganese chloride	increases abundance, increases expression, affects cotreatment	1
jinfukang	decreases expression	1
3-(2-hydroxy-4-(2-methylnonan-2-yl)phenyl)cyclohexan-1-ol	increases expression	1
Sunitinib	decreases expression	1
Benzo(a)pyrene	affects methylation	1
Cadmium	affects reaction, decreases expression	1
Hydrogen Peroxide	affects expression	1
Manganese	increases abundance, increases expression, affects cotreatment	1
Methyl Methanesulfonate	increases expression	1
Ozone	increases abundance, affects expression	1
Quercetin	decreases expression	1
Rotenone	decreases expression	1
Tunicamycin	increases expression	1
Cyclosporine	increases expression	1
Cadmium Chloride	decreases expression	1
Lactic Acid	decreases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
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
NCT00699101	PHASE4	TERMINATED	Using the Conture® Multi-Lumen Balloon to Deliver Accelerated Partial Breast Brachytherapy
NCT00742222	PHASE4	COMPLETED	Electronic Xoft Intersociety Brachytherapy Trial: Electronic Brachytherapy (EBT) For Treatment of Early Stage Breast Cancer
NCT00754767	PHASE4	TERMINATED	L-Carnitine L-Tartrate in Preventing Peripheral Neuropathy Caused By Chemotherapy in Women With Metastatic Breast Cancer