IGSF1

Summary

IGSF1 (immunoglobulin superfamily member 1, HGNC:5948) is a protein-coding gene on chromosome Xq26.1, encoding Immunoglobulin superfamily member 1 (Q8N6C5). Seems to be a coreceptor in inhibin signaling, but seems not to be a high-affinity inhibin receptor.

This gene encodes a member of the immunoglobulin-like domain-containing superfamily. Proteins in this superfamily contain varying numbers of immunoglobulin-like domains and are thought to participate in the regulation of interactions between cells. Multiple transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 3547 — RefSeq curated summary.

At a glance

• Gene–disease (curated): X-linked central congenital hypothyroidism with late-onset testicular enlargement (Definitive, GenCC)
• GWAS associations: 2
• Clinical variants (ClinVar): 486 total — 20 pathogenic, 6 likely-pathogenic
• Phenotypes (HPO): 6
• MANE Select transcript: NM_001555

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:5948
Approved symbol	IGSF1
Name	immunoglobulin superfamily member 1
Location	Xq26.1
Locus type	gene with protein product
Status	Approved
Aliases	KIAA0364, IGDC1, IGCD1, INHBP, MGC75490, PGSF2
Ensembl gene	ENSG00000147255
Ensembl biotype	protein_coding
OMIM	300137
Entrez	3547

Gene structure

Transcript identifiers

Ensembl transcripts: 21 — 15 protein_coding, 4 retained_intron, 2 protein_coding_CDS_not_defined

ENST00000361420, ENST00000370900, ENST00000370901, ENST00000370903, ENST00000370904, ENST00000370910, ENST00000467244, ENST00000469836, ENST00000650730, ENST00000650945, ENST00000651212, ENST00000651402, ENST00000651526, ENST00000651556, ENST00000651744, ENST00000652004, ENST00000652189, ENST00000864056, ENST00000930398, ENST00000966718, ENST00000966719

RefSeq mRNA: 5 — MANE Select: NM_001555 NM_001170961, NM_001170962, NM_001170963, NM_001555, NM_205833

CCDS: CCDS14629, CCDS14630, CCDS55490, CCDS55491

Canonical transcript exons

ENST00000361420 — 20 exons

Exon	Start	End
ENSE00000979368	131286437	131286463
ENSE00000979369	131285767	131286048
ENSE00000979371	131282980	131283264
ENSE00000979373	131281666	131281944
ENSE00000979374	131281218	131281338
ENSE00000979375	131279271	131279341
ENSE00000979376	131279143	131279175
ENSE00000979377	131278461	131278751
ENSE00000979378	131277856	131278134
ENSE00000979379	131276939	131277226
ENSE00000979380	131275961	131276248
ENSE00000979381	131275478	131275765
ENSE00000979382	131274999	131275286
ENSE00000979383	131274599	131274877
ENSE00000979384	131274083	131274206
ENSE00001358631	131285179	131285466
ENSE00001436200	131282444	131282737
ENSE00001453889	131273506	131273931
ENSE00001661857	131286605	131286741
ENSE00001856366	131289214	131289306

Expression profiles

Bgee: expression breadth ubiquitous, 194 present calls, max score 98.45.

FANTOM5 (CAGE): breadth broad, TPM avg 7.8105 / max 999.6224, expressed in 559 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
200484	7.0546	543
200482	0.4985	194
200483	0.1116	55
209811	0.0728	33
200485	0.0441	12
200481	0.0290	17

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
pituitary gland	UBERON:0000007	98.45	gold quality
adenohypophysis	UBERON:0002196	97.70	gold quality
right atrium auricular region	UBERON:0006631	89.81	gold quality
hypothalamus	UBERON:0001898	89.52	gold quality
cardiac atrium	UBERON:0002081	87.77	gold quality
tibial nerve	UBERON:0001323	86.89	gold quality
nucleus accumbens	UBERON:0001882	86.41	gold quality
apex of heart	UBERON:0002098	85.80	gold quality
left testis	UBERON:0004533	84.86	gold quality
right testis	UBERON:0004534	84.32	gold quality
adrenal tissue	UBERON:0018303	83.42	gold quality
substantia nigra	UBERON:0002038	82.89	gold quality
caudate nucleus	UBERON:0001873	82.51	gold quality
testis	UBERON:0000473	81.95	gold quality
midbrain	UBERON:0001891	81.14	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	80.99	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	80.73	gold quality
spinal cord	UBERON:0002240	80.00	gold quality
islet of Langerhans	UBERON:0000006	79.66	gold quality
putamen	UBERON:0001874	79.01	gold quality
endometrium epithelium	UBERON:0004811	78.20	silver quality
left lobe of thyroid gland	UBERON:0001120	77.69	gold quality
heart	UBERON:0000948	77.37	gold quality
thyroid gland	UBERON:0002046	75.97	gold quality
amygdala	UBERON:0001876	75.94	gold quality
left uterine tube	UBERON:0001303	75.85	gold quality
forebrain	UBERON:0001890	75.63	gold quality
heart left ventricle	UBERON:0002084	75.30	gold quality
right lobe of thyroid gland	UBERON:0001119	75.21	gold quality
prefrontal cortex	UBERON:0000451	75.00	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-MTAB-5061	yes	6.32
E-ANND-3	yes	5.67

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

15 targeting IGSF1, 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-6758-5P	100.00	66.21	1470
HSA-MIR-6856-5P	100.00	65.47	1298
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-185-3P	99.95	67.01	1743
HSA-MIR-545-5P	99.66	70.18	2308
HSA-MIR-3616-5P	99.55	67.02	989
HSA-MIR-573	99.55	67.44	955
HSA-MIR-4489	99.50	65.56	785
HSA-MIR-593-3P	99.22	67.28	1327
HSA-MIR-892C-5P	99.16	70.56	2116
HSA-MIR-6761-5P	98.71	68.03	1504
HSA-MIR-6784-3P	98.39	64.88	662
HSA-MIR-4670-3P	97.37	68.35	1378
HSA-MIR-125A-3P	97.04	66.92	902
HSA-MIR-582-3P	96.69	67.38	1019

Literature-anchored findings (GeneRIF, showing 19)

• IgSF1 is processed through sequential proteolysis by signal peptidase and signal peptide peptidase (PMID:18981173)
• Using exome and candidate gene sequencing, 8 distinct mutations and 2 deletions in IGSF1 were identified in males from 11 unrelated families with central hypothyroidism, testicular enlargement and variably low prolactin concentrations. (PMID:23143598)
• Our findings provide additional genetic evidence that loss-of-function mutations in IGSF1 cause an X-linked form of C-CH and variable prolactin deficiency. (PMID:23966245)
• Data suggest male subjects with IGSF1 deficiency syndrome exhibit X-linked congenital/central hypothyroidism, delayed puberty, macro-orchidism, hypoprolactinemia, metabolic syndrome, and transient partial growth hormone deficiency. [CASE REPORTS] (PMID:24108313)
• There is insufficient evidence to conclude that the three observed VUCSs in IGSF1 are associated with CDGP, making it unlikely that IGSF1 mutations are a prevalent cause of CDGP. (PMID:25354429)
• Immunohistochemistry showed increased IGSF1 staining in the GH-producing tumor from the patient with the IGSF1 p.N604T variant compared with a GH-producing adenoma from a patient negative for any IGSF1 variants and with normal control pituitary tissue. (PMID:25527509)
• This case suggests that more attention should be paid to intrauterine growth and birth history when patients are suspected of having an IGSF1 mutation (PMID:26302767)
• Adult male patients with IGSF1 deficiency exhibit mild deficits in attentional control on formal testing. (PMID:26387489)
• IGSF1 Deficiency is associated with X-linked IGSF1 deficiency syndrome. (PMID:26840047)
• Individuals with identical IGSF1 deletions can exhibit variable pituitary hormone deficiencies, of which overt TSH deficiency is the most consistent feature (PMID:27146357)
• We identified a novel insertion mutation in the IGSF1 gene and further delineated the phenotype of the IGSF1-deficiency syndrome. Our findings indicate a possible association between an IGSF1 mutation and neurological phenotypes. (PMID:27310681)
• A novel mutation (c.2713C>T, p.Q905X) of the IGSF1 gene was identified that causes congenital central hypothyroidism in a Japanese family. The findings further expand the clinical heterogeneity of this entity. (PMID:27762734)
• IGSF1 defect was the leading genetic cause of Congenital Isolated TSH Deficiency. (PMID:31504637)
• somatotrope neurosecretory hyperfunction in IGSF1-deficient humans and mice. (PMID:31650157)
• Congenital Central Hypothyroidism Caused by a Novel IGSF1 Variant Identified in a French Family. (PMID:35350016)
• Case Report: A Detailed Phenotypic Description of Patients and Relatives with Combined Central Hypothyroidism and Growth Hormone Deficiency Carrying IGSF1 Mutations. (PMID:35456429)
• IGSF1 mutations are the most frequent genetic aetiology of thyrotropin deficiency. (PMID:36201163)
• IGSF1 mutation as a cause of isolated central hypothyroidism. (PMID:36464600)
• [Clinical characteristics and genetic analysis of four patients with central hypothyroidism due to IGSF1 gene variants]. (PMID:36854408)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Igsf1	ENSMUSG00000031111
rattus_norvegicus	Igsf1	ENSRNOG00000007600

Paralogs (25): GP6 (ENSG00000088053), LILRB1 (ENSG00000104972), LILRA1 (ENSG00000104974), LILRB5 (ENSG00000105609), A1BG (ENSG00000121410), KIR2DL1 (ENSG00000125498), LILRB2 (ENSG00000131042), LAIR2 (ENSG00000167618), KIR3DL1 (ENSG00000167633), OSCAR (ENSG00000170909), FCAR (ENSG00000186431), LILRB4 (ENSG00000186818), LILRA5 (ENSG00000187116), KIR2DL4 (ENSG00000189013), VSTM1 (ENSG00000189068), NCR1 (ENSG00000189430), LILRB3 (ENSG00000204577), KIR2DS4 (ENSG00000221957), LILRA4 (ENSG00000239961), LILRA2 (ENSG00000239998), KIR3DL2 (ENSG00000240403), KIR3DL3 (ENSG00000242019), KIR2DL3 (ENSG00000243772), LILRA6 (ENSG00000244482), TARM1 (ENSG00000248385)

Protein

Protein identifiers

Immunoglobulin superfamily member 1 — Q8N6C5 (reviewed: Q8N6C5)

Alternative names: Immunoglobulin-like domain-containing protein 1, Inhibin-binding protein, Pituitary gland-specific factor 2, p120

All UniProt accessions (5): Q8N6C5, A0A494C0E7, A0A494C0H8, A0A494C0K8, A0A494C0W8

UniProt curated annotations — full annotation on UniProt →

Function. Seems to be a coreceptor in inhibin signaling, but seems not to be a high-affinity inhibin receptor. Antagonizes activin A signaling in the presence or absence of inhibin B. Necessary to mediate a specific antagonistic effect of inhibin B on activin-stimulated transcription.

Subunit / interactions. Interacts with INHA. In PubMed:12385827 does not interact with INHA; standard receptor binding assay. Interacts with ACVR1B; the interaction appears to be ligand-dependent as it is diminished by inhibin B and activin A. Interacts with ACVR2A, ACVR2B, ACVRL1 and BMPR1B. Interacts with HECTD1.

Subcellular location. Membrane Membrane Secreted.

Tissue specificity. Highly expressed in pancreas, testis and fetal liver. Moderately expressed in heart, prostate and small intestine. Expressed at very low levels in brain, thymus, ovary, colon, fetal lung and fetal kidney. Expressed in muscle. Isoform 3 is expressed in pituitary gland.

Disease relevance. Hypothyroidism, central, and testicular enlargement (CHTE) [MIM:300888] A disorder characterized by insufficient thyroid gland stimulation by thyroid stimulating hormone (TSH), resulting from hypothalamic and/or pituitary dysfunction. CHTE patients have delayed testosterone increase at puberty with normal testosterone levels in adulthood, normal testicular volume in childhood and enlarged testicles in adulthood. The disease is caused by variants affecting the gene represented in this entry.

Isoforms (4)

UniProt ID	Names	Canonical?
Q8N6C5-1	1, InhBP-L, long	yes
Q8N6C5-2	2
Q8N6C5-3	3, InhBP-S, short
Q8N6C5-4	4

RefSeq proteins (5): NP_001164432, NP_001164433, NP_001164434, NP_001546, NP_991402 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003598	Ig_sub2	Domain
IPR003599	Ig_sub	Domain
IPR007110	Ig-like_dom	Domain
IPR013783	Ig-like_fold	Homologous_superfamily
IPR036179	Ig-like_dom_sf	Homologous_superfamily
IPR050412	Ig-like_Receptors_ImmuneReg	Family

Pfam: PF13895

UniProt features (58 total): glycosylation site 14, domain 12, disulfide bond 9, sequence variant 6, splice variant 4, sequence conflict 4, topological domain 3, transmembrane region 2, signal peptide 1, chain 1, region of interest 1, compositionally biased region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8N6C5-F1	73.64	0.11

Functional residue map

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

Disulfide bonds (9): 58–106, 248–296, 343–392, 441–484, 703–750, 799–849, 895–942, 1087–1134, 1183–1226

Glycosylation sites (14): 53, 338, 374, 381, 607, 747, 798, 846, 939, 986, 1027, 1082, 1147, 1223

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 104 (showing top): FOXO1_01, GGGTGGRR_PAX4_03, ACEVEDO_LIVER_CANCER_WITH_H3K27ME3_UP, PATIL_LIVER_CANCER, CREIGHTON_ENDOCRINE_THERAPY_RESISTANCE_1, GOBP_REGULATION_OF_TRANSMEMBRANE_RECEPTOR_PROTEIN_SERINE_THREONINE_KINASE_SIGNALING_PATHWAY, MODULE_88, GOBP_ACTIVIN_RECEPTOR_SIGNALING_PATHWAY, TGGNNNNNNKCCAR_UNKNOWN, GOMF_SIGNALING_RECEPTOR_BINDING, GOBP_NEGATIVE_REGULATION_OF_TRANSMEMBRANE_RECEPTOR_PROTEIN_SERINE_THREONINE_KINASE_SIGNALING_PATHWAY, GOBP_REGULATION_OF_ACTIVIN_RECEPTOR_SIGNALING_PATHWAY, MODULE_55, GOMF_TRANSMEMBRANE_SIGNALING_RECEPTOR_ACTIVITY, MYB_Q6

GO Biological Process (3): immune response-regulating signaling pathway (GO:0002764), regulation of DNA-templated transcription (GO:0006355), negative regulation of activin receptor signaling pathway (GO:0032926)

GO Molecular Function (3): inhibin binding (GO:0034711), activin receptor antagonist activity (GO:0038102), protein binding (GO:0005515)

GO Cellular Component (2): extracellular region (GO:0005576), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
signal transduction	1
regulation of immune response	1
DNA-templated transcription	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
activin receptor signaling pathway	1
regulation of activin receptor signaling pathway	1
negative regulation of transmembrane receptor protein serine/threonine kinase signaling pathway	1
protein binding	1
negative regulation of activin receptor signaling pathway	1
receptor antagonist activity	1
binding	1

Protein interactions and networks

STRING

712 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
IGSF1	INHBA	P08476	845
IGSF1	TRHR	P34981	651
IGSF1	TSHB	P01222	621
IGSF1	RTN4R	Q9BZR6	536
IGSF1	LINGO1	Q96FE5	507
IGSF1	PROP1	O75360	479
IGSF1	H3BTC1	H3BTC1	478
IGSF1	IRS4	O14654	478
IGSF1	TRH	P20396	476
IGSF1	POU1F1	P28069	447
IGSF1	HESX1	Q9UBX0	444
IGSF1	LGALSL	Q3ZCW2	440
IGSF1	OR13H1	Q8NG92	419
IGSF1	LHX4	Q969G2	410
IGSF1	IGSF22	Q8N9C0	400

IntAct

11 interactions, top by confidence:

A	B	Type	Score
SLC15A4	PGRMC1	psi-mi:“MI:0914”(association)	0.530
ANKH	FAM234B	psi-mi:“MI:0914”(association)	0.530
FLVCR1	TNFRSF10B	psi-mi:“MI:0914”(association)	0.530
IGSF1	RPL8	psi-mi:“MI:0915”(physical association)	0.400
IGSF1	HECTD1	psi-mi:“MI:0915”(physical association)	0.370
IGSF1	RANBP10	psi-mi:“MI:0915”(physical association)	0.370
NEK4	E2F8	psi-mi:“MI:0914”(association)	0.350
BMI1	MEIS3P1	psi-mi:“MI:0914”(association)	0.350
GPC3	PXDNL	psi-mi:“MI:0914”(association)	0.350
SLC16A2	TNFRSF10B	psi-mi:“MI:0914”(association)	0.350

BioGRID (25): IGSF1 (Proximity Label-MS), IGSF1 (Affinity Capture-MS), IGF1 (Two-hybrid), IGSF1 (Affinity Capture-MS), KCNC1 (Co-fractionation), NPTX1 (Co-fractionation), PAPPA (Co-fractionation), TSC2 (Co-fractionation), IGSF1 (Cross-Linking-MS (XL-MS)), IGSF1 (Affinity Capture-MS), IGSF1 (Affinity Capture-MS), IGSF1 (Affinity Capture-MS), INHBA (Co-localization), INHBB (Co-localization), IGSF1 (Affinity Capture-Western)

ESM2 similar proteins: A0A0G2KBC9, A1YIY0, B6A8R8, C0HJX2, C0HJX3, D3ZQX2, P08101, P0C1X9, P0DTI4, P12314, P12318, P26151, P43626, P43627, P43628, P43629, P43630, P43631, P43632, P83555, P83556, P97484, Q01965, Q13291, Q14943, Q14952, Q14953, Q14954, Q28942, Q3B8P2, Q60513, Q61450, Q63203, Q64281, Q68SN8, Q6UX27, Q7TQA1, Q7Z6M3, Q8BG84, Q8BHK6

Diamond homologs: A0A0G2KBC9, A6NI73, B6A8R8, C0HJX2, C0HJX3, D3ZQX2, O75019, O75022, O75023, O76036, P0C191, P0C1X9, P24071, P43626, P43627, P43628, P43629, P43630, P43631, P43632, P59901, P83555, P83556, P97484, Q14943, Q14952, Q14953, Q14954, Q61450, Q64281, Q6GTX8, Q6ISS4, Q6PI73, Q7TQA1, Q863H2, Q8C567, Q8IYS5, Q8MJZ2, Q8MJZ7, Q8N109

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	20
Likely pathogenic	6
Uncertain significance	143
Likely benign	66
Benign	36

Top pathogenic / likely-pathogenic (26)

Variant ID	HGVS	Classification
1033351	NM_001555.5(IGSF1):c.3550C>T (p.Arg1184Ter)	Pathogenic
1284394	NM_001555.5(IGSF1):c.1966G>A (p.Gly656Arg)	Pathogenic
1301901	NM_001555.5(IGSF1):c.3790C>T (p.Arg1264Ter)	Pathogenic
1526850	GRCh37/hg19 Xq26.1-26.2(chrX:130299561-131090813)	Pathogenic
1695315	NM_001555.5(IGSF1):c.3763C>T (p.Gln1255Ter)	Pathogenic
1703440	NM_001555.5(IGSF1):c.70+1G>A	Pathogenic
2661439	NM_001555.5(IGSF1):c.3043G>T (p.Gly1015Ter)	Pathogenic
3108778	NM_001555.5(IGSF1):c.1814_1836dup (p.Arg613delinsGlyArgThrTer)	Pathogenic
3377347	NM_001555.5(IGSF1):c.461_486del (p.Gly154fs)	Pathogenic
3377351	NM_001555.5(IGSF1):c.404_407del (p.Trp135fs)	Pathogenic
39849	NM_001555.5(IGSF1):c.2123_2149del (p.Ala708_Lys716del)	Pathogenic
39850	NM_001555.5(IGSF1):c.2916G>A (p.Trp972Ter)	Pathogenic
39851	NM_001555.5(IGSF1):c.2233del (p.Glu745fs)	Pathogenic
39852	NM_001555.5(IGSF1):c.2573C>T (p.Ser858Phe)	Pathogenic
39853	NM_001555.5(IGSF1):c.3581dup (p.Glu1195fs)	Pathogenic
4037877	NM_001555.5(IGSF1):c.2175del (p.Gln725fs)	Pathogenic
451530	NM_001555.5(IGSF1):c.2896+1del	Pathogenic
4683155	NM_001555.5(IGSF1):c.257_264dup (p.Val89fs)	Pathogenic
689654	NM_001555.5(IGSF1):c.2268dup (p.Arg757fs)	Pathogenic
689655	NM_001555.5(IGSF1):c.2303T>C (p.Leu768Pro)	Pathogenic
2440886	NM_001555.5(IGSF1):c.2042-1_2042del	Likely pathogenic
2585310	NM_001555.5(IGSF1):c.1614G>A (p.Trp538Ter)	Likely pathogenic
3764642	NM_001555.5(IGSF1):c.3868C>T (p.Arg1290Ter)	Likely pathogenic
4291707	NM_001555.5(IGSF1):c.2816_2819dup (p.Tyr940Ter)	Likely pathogenic
4755483	NM_001555.5(IGSF1):c.2036_2037insA (p.Thr680fs)	Likely pathogenic
489337	NM_001555.5(IGSF1):c.1324C>T (p.Arg442Ter)	Likely pathogenic

SpliceAI

3485 predictions. Top by Δscore:

Variant	Effect	Δscore
X:131273928:GCCT:G	acceptor_gain	1.0000
X:131273929:CCTC:C	acceptor_gain	1.0000
X:131273930:CT:C	acceptor_gain	1.0000
X:131273932:C:CC	acceptor_gain	1.0000
X:131273934:A:C	acceptor_gain	1.0000
X:131274873:CTTAT:C	acceptor_gain	1.0000
X:131274874:TTAT:T	acceptor_gain	1.0000
X:131274878:C:CC	acceptor_gain	1.0000
X:131274878:C:CG	acceptor_loss	1.0000
X:131274879:T:G	acceptor_loss	1.0000
X:131277852:CTACC:C	donor_loss	1.0000
X:131277853:TAC:T	donor_loss	1.0000
X:131277855:CCT:C	donor_loss	1.0000
X:131279080:CGCT:C	donor_gain	1.0000
X:131279337:CTTCT:C	acceptor_gain	1.0000
X:131279340:CT:C	acceptor_gain	1.0000
X:131279342:C:CC	acceptor_gain	1.0000
X:131279352:C:CT	acceptor_gain	1.0000
X:131279352:C:T	acceptor_gain	1.0000
X:131279353:A:T	acceptor_gain	1.0000
X:131286603:A:AC	donor_gain	1.0000
X:131286604:C:CC	donor_gain	1.0000
X:131273927:AGCCT:A	acceptor_gain	0.9900
X:131273933:T:A	acceptor_loss	0.9900
X:131273934:A:AC	acceptor_gain	0.9900
X:131273936:G:C	acceptor_gain	0.9900
X:131274593:TCTTA:T	donor_loss	0.9900
X:131274594:CTTAC:C	donor_loss	0.9900
X:131274595:TTA:T	donor_loss	0.9900
X:131274596:TA:T	donor_loss	0.9900

AlphaMissense

8714 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
X:131274802:C:G	C1183S	0.997
X:131274803:A:G	C1183R	0.997
X:131274803:A:T	C1183S	0.997
X:131278523:C:G	C660S	0.997
X:131278524:A:G	C660R	0.997
X:131278524:A:T	C660S	0.997
X:131278530:A:C	Y658D	0.997
X:131278568:A:C	F645C	0.997
X:131278568:A:G	F645S	0.997
X:131278636:A:C	F622L	0.997
X:131278636:A:T	F622L	0.997
X:131278638:A:G	F622L	0.997
X:131278667:C:G	C612S	0.997
X:131278668:A:G	C612R	0.997
X:131278668:A:T	C612S	0.997
X:131274672:G:C	C1226W	0.996
X:131274674:A:G	C1226R	0.996
X:131278486:A:C	S672R	0.996
X:131278486:A:T	S672R	0.996
X:131278488:T:G	S672R	0.996
X:131278513:C:A	W663C	0.996
X:131278513:C:G	W663C	0.996
X:131278522:G:C	C660W	0.996
X:131278631:A:G	L624S	0.996
X:131278637:A:C	F622C	0.996
X:131278666:G:C	C612W	0.996
X:131274673:C:G	C1226S	0.995
X:131274673:C:T	C1226Y	0.995
X:131274674:A:T	C1226S	0.995
X:131274774:A:C	F1192L	0.995

dbSNP variants (sampled 300 via entrez): RS1000446653 (X:131290489 A>G), RS1000560641 (X:131290175 C>T), RS1000716211 (X:131290242 T>C), RS1000854247 (X:131283964 G>C), RS1001086411 (X:131289757 G>A), RS1001742736 (X:131286333 A>G,T), RS1002255009 (X:131278188 G>T), RS1002281527 (X:131277471 G>A), RS1002943178 (X:131281064 G>A), RS1003272470 (X:131285966 G>C,T), RS1003404697 (X:131281620 T>A), RS1003501926 (X:131274907 G>T), RS1003852236 (X:131273447 C>T), RS1004053259 (X:131273873 C>T), RS1004197876 (X:131287930 G>C)

Disease associations

OMIM: gene MIM:300137 | disease phenotypes: MIM:300888, MIM:275200

GenCC curated gene-disease

Disease	Classification	Inheritance
X-linked central congenital hypothyroidism with late-onset testicular enlargement	Definitive	X-linked

Mondo (2): X-linked central congenital hypothyroidism with late-onset testicular enlargement (MONDO:0010475), hypothyroidism due to TSH receptor mutations (MONDO:0010142)

Orphanet (2): X-linked central congenital hypothyroidism with late-onset testicular enlargement (Orphanet:329235), Hypothyroidism due to TSH receptor mutations (Orphanet:90673)

HPO phenotypes

6 total (6 of 6 shown, HPO-id order):

HPO	Term
HP:0000821	Hypothyroidism
HP:0001419	X-linked recessive inheritance
HP:0008202	Reduced circulating prolactin concentration
HP:0025502	Overweight
HP:0033075	Inappropriately normal thyroid-stimulating hormone level
HP:0033082	Reduced TSH response to thyrotrophin-releasing hormone stimulation test

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST003993_29	Menarche (age at onset)	7.000000e-12
GCST003994_13	Age at voice drop	2.000000e-10

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004703	age at menarche
EFO:0007888	age at voice drop

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	increases expression, affects expression	3
Benzo(a)pyrene	affects methylation, increases expression	2
Estradiol	affects cotreatment, decreases expression, increases expression	2
Cyclosporine	decreases expression	2
dicrotophos	increases expression	1
methylmercuric chloride	decreases expression	1
propionaldehyde	increases expression	1
bisphenol A	affects cotreatment, decreases methylation	1
deoxynivalenol	decreases expression	1
testosterone undecanoate	affects cotreatment, decreases expression	1
trichostatin A	increases expression	1
butyraldehyde	decreases expression	1
nickel chloride	decreases expression	1
perfluorooctanoic acid	affects cotreatment, decreases expression	1
pentanal	increases expression	1
2,3-dimethoxy-1,4-naphthoquinone	decreases expression	1
CGP 52608	affects binding, increases reaction	1
K 7174	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
Grape Seed Proanthocyanidins	affects cotreatment, increases expression	1
dorsomorphin	decreases expression, affects cotreatment	1
Sunitinib	decreases expression	1
Fulvestrant	affects cotreatment, decreases methylation	1
Vorinostat	decreases expression	1
Aldehydes	increases expression	1
Caffeine	affects phosphorylation	1
Catechin	affects cotreatment, increases expression	1
Cosmetics	decreases expression, affects cotreatment	1
Doxorubicin	decreases expression	1
Flame Retardants	affects cotreatment, decreases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT03655223	Not specified	ENROLLING_BY_INVITATION	Early Check: Expanded Screening in Newborns