TONSL

Summary

TONSL (tonsoku like, DNA repair protein, HGNC:7801) is a protein-coding gene on chromosome 8q24.3, encoding Tonsoku-like protein (Q96HA7). Component of the MMS22L-TONSL complex, a complex that promotes homologous recombination-mediated repair of double-strand breaks (DSBs) at stalled or collapsed replication forks. It is a common-essential gene (DepMap: required in 99.7% of cancer cell lines).

The protein encoded by this gene is thought to be a negative regulator of NF-kappa-B mediated transcription. The encoded protein may bind NF-kappa-B complexes and trap them in the cytoplasm, preventing them from entering the nucleus and interacting with the DNA. Phosphorylation of this protein targets it for degradation by the ubiquitination pathway, which frees the NF-kappa-B complexes to enter the nucleus.

Source: NCBI Gene 4796 — RefSeq curated summary.

At a glance

• Gene–disease (curated): spondyloepimetaphyseal dysplasia, sponastrime type (Definitive, GenCC)
• GWAS associations: 3
• Clinical variants (ClinVar): 1,301 total — 46 pathogenic, 29 likely-pathogenic
• Phenotypes (HPO): 97
• Cancer dependency (DepMap): dependent in 99.7% of screened cell lines (common-essential)
• MANE Select transcript: NM_013432

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:7801
Approved symbol	TONSL
Name	tonsoku like, DNA repair protein
Location	8q24.3
Locus type	gene with protein product
Status	Approved
Aliases	IKBR
Ensembl gene	ENSG00000160949
Ensembl biotype	protein_coding
OMIM	604546
Entrez	4796

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 6 protein_coding, 1 retained_intron

ENST00000409379, ENST00000497613, ENST00000932054, ENST00000932055, ENST00000932056, ENST00000971177, ENST00000971178

RefSeq mRNA: 1 — MANE Select: NM_013432 NM_013432

CCDS: CCDS34968

Canonical transcript exons

ENST00000409379 — 26 exons

Exon	Start	End
ENSE00001055628	144440966	144441111
ENSE00001055634	144440718	144440870
ENSE00001055648	144433588	144433759
ENSE00001137603	144432285	144432460
ENSE00001287694	144442241	144442412
ENSE00001298624	144442037	144442151
ENSE00001329051	144428775	144429336
ENSE00001587091	144444390	144444440
ENSE00001613225	144443138	144443321
ENSE00001642616	144442677	144442806
ENSE00001674788	144444180	144444275
ENSE00001688428	144443882	144444024
ENSE00003463561	144438653	144438735
ENSE00003464742	144436558	144436681
ENSE00003469827	144435474	144435550
ENSE00003475516	144433978	144434279
ENSE00003485485	144438471	144438560
ENSE00003545816	144437027	144437099
ENSE00003548803	144435658	144436418
ENSE00003553698	144430404	144430537
ENSE00003595215	144434811	144434889
ENSE00003614377	144436757	144436920
ENSE00003672436	144440351	144440476
ENSE00003672780	144431078	144431151
ENSE00003675195	144440021	144440210
ENSE00003686562	144435017	144435170

Expression profiles

Bgee: expression breadth ubiquitous, 155 present calls, max score 82.29.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 5.9535 / max 126.4349, expressed in 1164 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
95683	5.9535	1164

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
mucosa of transverse colon	UBERON:0004991	82.29	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	81.45	gold quality
ventricular zone	UBERON:0003053	81.05	gold quality
ganglionic eminence	UBERON:0004023	77.58	gold quality
granulocyte	CL:0000094	76.48	gold quality
stromal cell of endometrium	CL:0002255	75.05	gold quality
lower esophagus mucosa	UBERON:0035834	74.06	gold quality
esophagus mucosa	UBERON:0002469	73.55	gold quality
small intestine Peyer’s patch	UBERON:0003454	72.96	gold quality
transverse colon	UBERON:0001157	72.75	gold quality
right adrenal gland	UBERON:0001233	71.82	gold quality
small intestine	UBERON:0002108	71.76	gold quality
apex of heart	UBERON:0002098	71.52	gold quality
right adrenal gland cortex	UBERON:0035827	71.18	gold quality
body of stomach	UBERON:0001161	71.12	gold quality
right lobe of thyroid gland	UBERON:0001119	70.99	gold quality
right hemisphere of cerebellum	UBERON:0014890	70.79	gold quality
jejunal mucosa	UBERON:0000399	70.74	silver quality
left lobe of thyroid gland	UBERON:0001120	70.50	gold quality
cerebellar hemisphere	UBERON:0002245	70.49	gold quality
cerebellar cortex	UBERON:0002129	70.42	gold quality
left adrenal gland	UBERON:0001234	70.02	gold quality
superficial temporal artery	UBERON:0001614	69.96	gold quality
spleen	UBERON:0002106	69.93	gold quality
left adrenal gland cortex	UBERON:0035825	69.78	gold quality
vermiform appendix	UBERON:0001154	69.74	gold quality
cerebellum	UBERON:0002037	69.46	gold quality
adrenal cortex	UBERON:0001235	69.14	gold quality
thyroid gland	UBERON:0002046	69.11	gold quality
skin of abdomen	UBERON:0001416	68.68	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	2.65

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

11 targeting TONSL, 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-4425	100.00	67.59	1049
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-4729	99.69	72.18	4233
HSA-MIR-504-3P	99.30	67.18	1745
HSA-MIR-7151-3P	99.04	69.72	2370
HSA-MIR-5089-5P	98.45	66.06	1388
HSA-MIR-6747-3P	97.73	64.84	1596
HSA-MIR-6085	96.57	64.11	621
HSA-MIR-6813-5P	94.68	64.20	588
HSA-MIR-6789-5P	94.05	66.19	285

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 99.7% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 16)

• These results indicate that MMS22L and TONSL are genome caretakers that stimulate the recombination-dependent repair of stalled or collapsed replication forks. (PMID:21055983)
• MMS22L and TONSL are required for the maintenance of genome stability. (PMID:21055984)
• This study identifies MMS22L-NFKBIL2 as components of the replication stress control pathway. (PMID:21055985)
• Results strongly suggest that the Mms22L-Nfkbil2 complex contributes to genome stability by regulating the chromatin state at stalled replication forks. (PMID:21113133)
• Common NFKBIL2 polymorphisms are associated with susceptibility to invasive pneumococcal infection. (PMID:21171993)
• new histones incorporated during DNA replication provide a signature of post-replicative chromatin, read by the human TONSL-MMS22L homologous recombination complex (PMID:27338793)
• By specifically regulating RAD51 activity at uncoupled replication forks, MMS22L-TONSL stabilizes perturbed replication forks by promoting replication fork reversal and stimulating their homologous recombination-mediated restart in vivo. (PMID:27797818)
• uncovered DNA-PKcs-dependent DNA damage-induced ASF1A phosphorylation, which enhances chromatin assembly, promoting MMS22L-TONSL recruitment and, hence, Rad51 loading. (PMID:29478807)
• TONSL holds promise for serving as a prognostic biomarker for hepatocellular carcinoma (PMID:30723051)
• Bi-allelic Variants in TONSL Cause SPONASTRIME Dysplasia and a Spectrum of Skeletal Dysplasia Phenotypes. (PMID:30773277)
• Mutations in TONSL Cause SPONASTRIME Dysplasia Phenotype. (PMID:30773278)
• The TONSL promoter is activated by TONSL-AS1. TONSL-AS1 was positively associated with TONSL in cancer tissues. The tumor-inhibiting effect of TONSL-AS1 in gastric cancer cells was associated with TONSL. (PMID:31158361)
• Novel TONSL variants cause SPONASTRIME dysplasia and associate with spontaneous chromosome breaks, defective cell proliferation and apoptosis. (PMID:32959051)
• MMS22L-TONSL functions in sister chromatid cohesion in a pathway parallel to DSCC1-RFC. (PMID:36622344)
• TONSL Is an Immortalizing Oncogene and a Therapeutic Target in Breast Cancer. (PMID:37057595)
• Oncogenic Impact of TONSL, a Homologous Recombination Repair Protein at the Replication Fork, in Cancer Stem Cells. (PMID:37298484)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	tonsl	ENSDARG00000071294
mus_musculus	Tonsl	ENSMUSG00000059323
rattus_norvegicus	Tonsl	ENSRNOG00000014703
drosophila_melanogaster	mask	FBGN0043884
caenorhabditis_elegans		WBGENE00011240

Paralogs (4): NFKBIA (ENSG00000100906), NFKBIB (ENSG00000104825), ANKRD22 (ENSG00000152766), PLA2G6 (ENSG00000184381)

Protein

Protein identifiers

Tonsoku-like protein — Q96HA7 (reviewed: Q96HA7)

Alternative names: Inhibitor of kappa B-related protein, NF-kappa-B inhibitor-like protein 2, Nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor-like 2

All UniProt accessions (1): Q96HA7

UniProt curated annotations — full annotation on UniProt →

Function. Component of the MMS22L-TONSL complex, a complex that promotes homologous recombination-mediated repair of double-strand breaks (DSBs) at stalled or collapsed replication forks. The MMS22L-TONSL complex is required to maintain genome integrity during DNA replication. It mediates the assembly of RAD51 filaments on single-stranded DNA (ssDNA): the MMS22L-TONSL complex is recruited to DSBs following histone replacement by histone chaperones and eviction of the replication protein A complex (RPA/RP-A) from DSBs. Following recruitment to DSBs, the TONSL-MMS22L complex promotes recruitment of RAD51 filaments and subsequent homologous recombination. Within the complex, TONSL acts as a histone reader, which recognizes and binds newly synthesized histones following their replacement by histone chaperones. Specifically binds histone H4 lacking methylation at ‘Lys-20’ (H4K20me0) and histone H3.1.

Subunit / interactions. Component of the MMS22L-TONSL complex, a complex at least composed of MMS22L and TONSL/NFKBIL2. Interacts with the MCM complex, the FACT complex and the RPA complex. Interacts with MCM5; the interaction is direct. Binds histones, with a strong preference for histone H3.1 (histones H3.1 and H3-4/H3.1t). Interacts (via ANK repeats) with histone H4; specifically binds histone H4 lacking methylation at ‘Lys-20’ (H4K20me0). May interact with DNAJC9; the interaction seems to be histone-dependent.

Subcellular location. Nucleus. Chromosome. Cytoplasm.

Tissue specificity. Expressed in heart, skeletal muscle and tracheal epithelial cells.

Disease relevance. Spondyloepimetaphyseal dysplasia, sponastrime type (SEMDSP) [MIM:271510] An autosomal recessive bone disease characterized by spine abnormalities, mid-face hypoplasia with a depressed nasal bridge, and striation of the metaphyses. Additional features include disproportionate short stature with exaggerated lumbar lordosis, scoliosis, coxa vara, limited elbow extension, small dysplastic epiphyses, childhood cataracts, short dental roots, and hypogammaglobulinemia. Disease severity and clinical manifestations are variable. Some patients have intellectual disability. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The ANK repeats mediate the interaction with the MCM complex and histones, while the LRR repeats mediate the interaction with MMS22L.

Similarity. Belongs to the Tonsoku family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q96HA7-1	1	yes
Q96HA7-2	2

RefSeq proteins (1): NP_038460* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001611	Leu-rich_rpt	Repeat
IPR002110	Ankyrin_rpt	Repeat
IPR011990	TPR-like_helical_dom_sf	Homologous_superfamily
IPR019734	TPR_rpt	Repeat
IPR032675	LRR_dom_sf	Homologous_superfamily
IPR036770	Ankyrin_rpt-contain_sf	Homologous_superfamily
IPR052311	MMS22L-TONSL_complex_comp	Family

Pfam: PF12796, PF13181, PF13516

UniProt features (79 total): sequence variant 26, repeat 18, compositionally biased region 8, helix 8, mutagenesis site 6, sequence conflict 5, region of interest 3, modified residue 2, chain 1, splice variant 1, turn 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
9WVH	X-RAY DIFFRACTION	1.96
9WVI	X-RAY DIFFRACTION	2.19
5JA4	X-RAY DIFFRACTION	2.42

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96HA7-F1	76.06	0.44

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 (2): 719, 797

Mutagenesis-validated functional residues (6):

Position	Phenotype
530	abolished interaction with histone h4 and recruitment to replication forks without affecting interaction with mms22l.
559	abolished interaction with histone h4 and recruitment to replication forks without affecting interaction with mms22l.
563	abolished interaction with histone h4 and recruitment to replication forks without affecting interaction with mms22l.
568	abolished interaction with histone h4 and recruitment to replication forks without affecting interaction with mms22l.
571	abolished interaction with histone h4 and recruitment to replication forks without affecting interaction with mms22l.
604	abolished interaction with histone h4 and recruitment to replication forks without affecting interaction with mms22l.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 336 (showing top): GOBP_DNA_TEMPLATED_DNA_REPLICATION_MAINTENANCE_OF_FIDELITY, RIZKI_TUMOR_INVASIVENESS_3D_DN, CAGCTG_AP4_Q5, GOCC_NUCLEAR_REPLICATION_FORK, SIG_CD40PATHWAYMAP, GOBP_PROTEIN_LOCALIZATION_TO_CHROMATIN, GOBP_PROTEIN_LOCALIZATION_TO_CHROMOSOME, GOBP_DNA_DAMAGE_RESPONSE, GOBP_PROTEIN_LOCALIZATION_TO_ORGANELLE, FISCHER_DREAM_TARGETS, GOBP_RECOMBINATIONAL_REPAIR, GOBP_DNA_REPLICATION, AP4_01, NUYTTEN_EZH2_TARGETS_DN, GOCC_MCM_COMPLEX

GO Biological Process (6): double-strand break repair via homologous recombination (GO:0000724), replication fork processing (GO:0031297), protein localization to chromatin (GO:0071168), DNA repair (GO:0006281), chromatin organization (GO:0006325), DNA damage response (GO:0006974)

GO Molecular Function (3): histone binding (GO:0042393), histone reader activity (GO:0140566), protein binding (GO:0005515)

GO Cellular Component (10): nucleoplasm (GO:0005654), cytoplasm (GO:0005737), nuclear body (GO:0016604), site of double-strand break (GO:0035861), nuclear replication fork (GO:0043596), nucleus (GO:0005634), DNA replication factor A complex (GO:0005662), chromosome (GO:0005694), FACT complex (GO:0035101), MCM complex (GO:0042555)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
intracellular membraneless organelle	2
recombinational repair	1
double-strand break repair	1
DNA-templated DNA replication maintenance of fidelity	1
protein localization to chromosome	1
DNA metabolic process	1
DNA damage response	1
cellular component organization	1
cellular response to stress	1
protein binding	1
nucleosome	1
histone binding	1
chromatin-protein adaptor activity	1
binding	1
nuclear lumen	1
intracellular anatomical structure	1
nucleoplasm	1
site of DNA damage	1
nuclear chromosome	1
nucleus	1
replication fork	1
CMG complex	1
intracellular membrane-bounded organelle	1
nuclear replisome	1
nuclear protein-containing complex	1
chromatin	1
transcription elongation factor complex	1
protein-containing complex	1
MCM core complex	1

Protein interactions and networks

STRING

3163 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TONSL	MMS22L	Q6ZRQ5	997
TONSL	NFKBIB	Q15653	637
TONSL	ASF1B	Q9NVP2	626
TONSL	SRSF1	Q07955	619
TONSL	NFKB2	Q00653	594
TONSL	RELB	Q01201	536
TONSL	SMARCAL1	Q9NZC9	528
TONSL	H3C1	P02295	501
TONSL	ADCK5	Q3MIX3	497
TONSL	REL	Q04864	486
TONSL	ZRANB3	Q5FWF4	455
TONSL	TMEM276	P0DTL5	454
TONSL	MCM5	P33992	452
TONSL	RELA	Q04206	445
TONSL	CPSF1	Q10570	432

IntAct

84 interactions, top by confidence:

A	B	Type	Score
MCM2	MCM4	psi-mi:“MI:0914”(association)	0.830
RFXANK	RFXAP	psi-mi:“MI:0914”(association)	0.780
H2AX	PPM1G	psi-mi:“MI:0914”(association)	0.730
H2AC4	PPM1G	psi-mi:“MI:0914”(association)	0.670
H2BC1	PPM1G	psi-mi:“MI:0914”(association)	0.640
ASF1B	HAT1	psi-mi:“MI:0914”(association)	0.640
MACROH2A2	PPM1G	psi-mi:“MI:0914”(association)	0.530
SSRP1	PARP1	psi-mi:“MI:0914”(association)	0.530
ASF1A	MCM4	psi-mi:“MI:0914”(association)	0.530
RPN1	APBB1	psi-mi:“MI:0914”(association)	0.530
H2BC26	PPM1G	psi-mi:“MI:0914”(association)	0.530
H2AC18	PPM1G	psi-mi:“MI:0914”(association)	0.530
H2AC20	PPM1G	psi-mi:“MI:0914”(association)	0.530
HSPB8	VWA8	psi-mi:“MI:0914”(association)	0.530
DAXX	TNRC18	psi-mi:“MI:0914”(association)	0.530
ANKRD22	ESYT2	psi-mi:“MI:0914”(association)	0.530
LPAR1	TMEM223	psi-mi:“MI:0914”(association)	0.530
TONSL	H2AC4	psi-mi:“MI:0914”(association)	0.530

BioGRID (171): TONSL (Affinity Capture-MS), TONSL (Synthetic Growth Defect), BRCA1 (Synthetic Growth Defect), TONSL (Co-localization), TONSL (Co-localization), TONSL (Co-localization), BRCA1 (Affinity Capture-Western), TONSL (Affinity Capture-MS), TONSL (Affinity Capture-MS), TONSL (Proximity Label-MS), HIST1H3E (Affinity Capture-Western), TONSL (Co-purification), TONSL (Affinity Capture-MS), TONSL (Affinity Capture-MS), TONSL (Affinity Capture-MS)

ESM2 similar proteins: A0A061IR73, A0A1B0GUU1, A6H687, A8MYJ7, B1WC39, D3ZVB0, E1BD59, G3MY25, G3MZC5, O75064, P07199, P27790, P29597, P48988, P52333, P52824, Q08DF2, Q0VCE3, Q13608, Q1JPD6, Q2VPB7, Q3TAP4, Q3U1Y4, Q3ZBE0, Q499M4, Q53EQ6, Q5JZY3, Q62137, Q63272, Q6B0B8, Q6DI92, Q6ZPS2, Q6ZS72, Q7TM95, Q80VI1, Q86UT6, Q8BYG9, Q8N9M5, Q8R5G7, Q8TE96

Diamond homologs: A9JR78, D4A615, Q0P5G1, Q6NZL6, Q96HA7, P10775, A1Z198, A6QLE5, B0FPE9, D4A523, D9I2F9, D9I2G1, D9I2G3, D9I2G4, D9I2H0, E9Q5R7, O15553, P13489, P29315, P33076, P59044, P59046, P59047, P79621, Q0GKD5, Q288C4, Q2LKU9, Q2LKV2, Q2LKV5, Q2LKW6, Q63035, Q647I9, Q6B966, Q7RTR0, Q86W24, Q86W25, Q86W26, Q86W28, Q8BU40, Q8CCN1

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 88 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
RNA Polymerase I Promoter Opening	10	32.3×	3e-11
DNA methylation	10	31.3×	3e-11
Packaging Of Telomere Ends	8	30.8×	2e-09
SIRT1 negatively regulates rRNA expression	10	29.9×	3e-11
Activated PKN1 stimulates transcription of AR (androgen receptor) regulated genes KLK2 and KLK3	10	29.5×	3e-11
Inhibition of DNA recombination at telomere	10	29.5×	3e-11
ChAHP complex assembly	9	29.1×	3e-10
Assembly of the ORC complex at the origin of replication	10	29.0×	3e-11

GO biological processes:

GO term	Partners	Fold	FDR
heterochromatin formation	8	25.2×	3e-07
nucleosome assembly	13	22.5×	9e-12
double-strand break repair	5	12.5×	5e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

1301 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	46
Likely pathogenic	29
Uncertain significance	550
Likely benign	562
Benign	51

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1343381	NM_013432.5(TONSL):c.787C>T (p.Arg263Ter)	Pathogenic
1455823	NM_013432.5(TONSL):c.706_725dup (p.Ser242fs)	Pathogenic
1456320	NM_013432.5(TONSL):c.2806C>T (p.Arg936Ter)	Pathogenic
1456359	NC_000008.10:g.(?145666498)(145668740_?)del	Pathogenic
1457804	NM_013432.5(TONSL):c.775_776del (p.Leu259fs)	Pathogenic
1457972	NM_013432.5(TONSL):c.2500del (p.Asp834fs)	Pathogenic
1805067	NM_013432.5(TONSL):c.3549del (p.Ser1183fs)	Pathogenic
1906671	NM_013432.5(TONSL):c.823A>T (p.Lys275Ter)	Pathogenic
1944597	NM_013432.5(TONSL):c.1885C>T (p.Arg629Ter)	Pathogenic
1955979	NM_013432.5(TONSL):c.182_192del (p.Asp61fs)	Pathogenic
1958280	NM_013432.5(TONSL):c.1353_1365del (p.Glu451fs)	Pathogenic
2002537	NM_013432.5(TONSL):c.2721del (p.Ser907fs)	Pathogenic
2012001	NM_013432.5(TONSL):c.2461dup (p.Gln821fs)	Pathogenic
2021891	NM_013432.5(TONSL):c.2376C>G (p.Tyr792Ter)	Pathogenic
2026439	NM_013432.5(TONSL):c.437del (p.Glu146fs)	Pathogenic
2094188	NM_013432.5(TONSL):c.3820_3821del (p.Leu1274fs)	Pathogenic
2116572	NM_013432.5(TONSL):c.2374_2375insG (p.Tyr792Ter)	Pathogenic
2124816	NM_013432.5(TONSL):c.1111del (p.Ala371fs)	Pathogenic
2132850	NM_013432.5(TONSL):c.2592del (p.Ser865fs)	Pathogenic
2134072	NM_013432.5(TONSL):c.2455_2456insA (p.Ala819fs)	Pathogenic
2697394	NM_013432.5(TONSL):c.3631C>T (p.Gln1211Ter)	Pathogenic
2814759	NM_013432.5(TONSL):c.3721C>T (p.Arg1241Ter)	Pathogenic
2837378	NM_013432.5(TONSL):c.2948_2949del (p.Glu983fs)	Pathogenic
2838273	NM_013432.5(TONSL):c.1162G>T (p.Glu388Ter)	Pathogenic
2875987	NC_000008.11:g.144433758CT[1]	Pathogenic
2977501	NM_013432.5(TONSL):c.3183_3184del (p.Leu1062fs)	Pathogenic
3245579	NC_000008.10:g.(?145657648)(145669797_?)del	Pathogenic
3460082	NM_013432.5(TONSL):c.1127del (p.Glu376fs)	Pathogenic
3613285	NM_013432.5(TONSL):c.3726C>G (p.Tyr1242Ter)	Pathogenic
3615675	NM_013432.5(TONSL):c.966del (p.Lys323fs)	Pathogenic

SpliceAI

3634 predictions. Top by Δscore:

Variant	Effect	Δscore
8:144429857:AAGC:A	donor_gain	1.0000
8:144430504:C:CT	acceptor_gain	1.0000
8:144430504:C:T	acceptor_gain	1.0000
8:144430505:A:T	acceptor_gain	1.0000
8:144430511:A:AC	acceptor_gain	1.0000
8:144430511:A:C	acceptor_gain	1.0000
8:144430515:G:GC	acceptor_gain	1.0000
8:144430535:CAT:C	acceptor_gain	1.0000
8:144432282:TA:T	donor_loss	1.0000
8:144432283:A:C	donor_loss	1.0000
8:144432284:CCT:C	donor_loss	1.0000
8:144432458:CAT:C	acceptor_gain	1.0000
8:144432459:ATC:A	acceptor_loss	1.0000
8:144432460:TCTGC:T	acceptor_loss	1.0000
8:144432461:C:CC	acceptor_gain	1.0000
8:144432461:CTGC:C	acceptor_loss	1.0000
8:144433758:CT:C	acceptor_gain	1.0000
8:144433760:C:CC	acceptor_gain	1.0000
8:144434277:CCC:C	acceptor_gain	1.0000
8:144434278:CCC:C	acceptor_gain	1.0000
8:144434280:C:CC	acceptor_gain	1.0000
8:144435012:CTCA:C	donor_loss	1.0000
8:144435013:TCA:T	donor_loss	1.0000
8:144435014:CACC:C	donor_loss	1.0000
8:144435016:C:A	donor_loss	1.0000
8:144435166:CACTG:C	acceptor_gain	1.0000
8:144435167:ACTG:A	acceptor_loss	1.0000
8:144435168:CTG:C	acceptor_gain	1.0000
8:144435171:C:CC	acceptor_gain	1.0000
8:144435171:CTGC:C	acceptor_loss	1.0000

AlphaMissense

8891 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
8:144437066:A:G	W563R	0.999
8:144437066:A:T	W563R	0.999
8:144437043:G:C	C570W	0.998
8:144437044:C:T	C570Y	0.998
8:144437064:C:A	W563C	0.998
8:144437064:C:G	W563C	0.998
8:144438513:G:C	C537W	0.998
8:144437059:G:T	P565H	0.997
8:144438514:C:T	C537Y	0.997
8:144436905:A:G	L581P	0.996
8:144437077:T:A	D559V	0.996
8:144436845:G:T	P601H	0.995
8:144436914:A:T	V578D	0.995
8:144437065:C:G	W563S	0.995
8:144437076:G:C	D559E	0.995
8:144437076:G:T	D559E	0.995
8:144437077:T:G	D559A	0.995
8:144438515:A:G	C537R	0.995
8:144436842:A:T	L602H	0.994
8:144437045:A:G	C570R	0.994
8:144437048:C:G	A569P	0.994
8:144437059:G:C	P565R	0.994
8:144437078:C:G	D559H	0.994
8:144436845:G:C	P601R	0.993
8:144438524:G:C	H534D	0.993
8:144438526:A:T	L533Q	0.993
8:144441025:C:A	G318W	0.993
8:144442691:G:C	S188R	0.993
8:144442691:G:T	S188R	0.993
8:144442693:T:G	S188R	0.993

dbSNP variants (sampled 300 via entrez): RS1000246275 (8:144442841 C>G), RS1000428237 (8:144444590 G>A), RS1000448460 (8:144428995 T>C), RS1000448780 (8:144438567 G>A), RS1000801214 (8:144429246 C>G,T), RS1001035461 (8:144443348 TGAGCC>T), RS1001516548 (8:144444509 C>G), RS1001677456 (8:144436340 C>T), RS1001897426 (8:144444358 C>A,T), RS1002119632 (8:144439715 C>G,T), RS1002328711 (8:144443992 G>A), RS1002426213 (8:144430746 T>G), RS1002531030 (8:144443257 C>A,T), RS1002585077 (8:144443008 C>T), RS1002672923 (8:144439008 C>T)

Disease associations

OMIM: gene MIM:604546 | disease phenotypes: MIM:271510

GenCC curated gene-disease

Disease	Classification	Inheritance
spondyloepimetaphyseal dysplasia, sponastrime type	Definitive	Autosomal recessive

Mondo (1): spondyloepimetaphyseal dysplasia, sponastrime type (MONDO:0010068)

Orphanet (1): SPONASTRIME dysplasia (Orphanet:93357)

HPO phenotypes

97 total (30 of 97 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000047	Hypospadias
HP:0000164	Abnormality of the dentition
HP:0000272	Malar flattening
HP:0000276	Long face
HP:0000286	Epicanthus
HP:0000303	Mandibular prognathia
HP:0000316	Hypertelorism
HP:0000414	Bulbous nose
HP:0000445	Wide nose
HP:0000463	Anteverted nares
HP:0000518	Cataract
HP:0000639	Nystagmus
HP:0000691	Microdontia
HP:0000696	Delayed eruption of permanent teeth
HP:0000821	Hypothyroidism
HP:0000826	Precocious puberty
HP:0000851	Congenital hypothyroidism
HP:0000925	Abnormality of the vertebral column
HP:0000926	Platyspondyly
HP:0000938	Osteopenia
HP:0001156	Brachydactyly
HP:0001169	Broad palm
HP:0001216	Delayed ossification of carpal bones
HP:0001249	Intellectual disability
HP:0001263	Global developmental delay
HP:0001377	Limited elbow extension
HP:0001382	Joint hypermobility
HP:0001511	Intrauterine growth retardation
HP:0001518	Small for gestational age

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST90002392_527	Mean corpuscular volume	4.000000e-10
GCST90002396_446	Mean reticulocyte volume	1.000000e-13
GCST90011900_204	Serum alkaline phosphatase levels	1.000000e-15

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0010701	mean reticulocyte volume
EFO:0004533	alkaline phosphatase measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C535786	Spondyloepimetaphyseal dysplasia, sponastrime type (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, increases expression	3
Valproic Acid	affects expression, decreases expression, increases methylation	3
Tobacco Smoke Pollution	decreases expression, increases methylation	2
aristolochic acid I	increases expression	1
FR900359	increases phosphorylation	1
dicrotophos	increases expression	1
bisphenol A	decreases methylation	1
arsenite	affects binding, decreases reaction	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
zinc chromate	decreases expression, increases abundance	1
di-n-butylphosphoric acid	affects expression	1
chromium hexavalent ion	decreases expression, increases abundance	1
abrine	decreases expression	1
2-methyl-2H-pyrazole-3-carboxylic acid (2-methyl-4-o-tolylazophenyl)amide	affects cotreatment, decreases expression	1
Sunitinib	decreases expression	1
Air Pollutants	decreases expression, increases abundance	1
Arsenic	affects methylation	1
Benzo(a)pyrene	increases expression	1
Calcitriol	decreases expression, affects cotreatment	1
Dichlorodiphenyl Dichloroethylene	increases expression	1
Oxygen	decreases expression	1
Quercetin	increases expression	1
Smoke	decreases expression	1
Testosterone	decreases expression, affects cotreatment	1
Tetrachlorodibenzodioxin	affects cotreatment, decreases expression	1
Urethane	decreases expression	1
Aflatoxin B1	increases methylation	1
Cadmium Chloride	decreases expression	1
Okadaic Acid	increases expression	1
Copper Sulfate	decreases expression	1

Clinical trials (associated diseases)

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