IGSF1

protein-coding

immunoglobulin superfamily member 1, the group of Immunoglobulin like domain containing

Gene summary

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.[provided by RefSeq, Jan 2010]

MANE transcript

NM_001555.5

Inheritance

ClinVar variants

P:35U:340B:89

Top phenotype

Central hypothyroidism and testicular enlargement

gnomAD constraint

pLI —, LoF o/e 0.1

Max pathogenic AF

—

Genomic locus

chrX:131,273,506-131,578,899

External References & Databases

Ensembl (ENSG00000147255)

Transcript & Mutation Effects

hg38 • Region Span ~305.4 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

X-linked central congenital hypothyroidism with late-onset testicular enlargementSUPPORTIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010475

Submitter: Orphanet

X-linked central congenital hypothyroidism with late-onset testicular enlargementSTRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010475

Submitter: PanelApp Australia

X-linked central congenital hypothyroidism with late-onset testicular enlargementSTRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010475

Submitter: Labcorp Genetics (formerly Invitae)

X-linked central congenital hypothyroidism with late-onset testicular enlargementDEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010475

Submitter: Ambry Genetics

X-linked central congenital hypothyroidism with late-onset testicular enlargementDEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010475

Submitter: G2P

Clinical Genomic Database (CGD)

Central hypothyroidism and testicular enlargementXL

Manifestation: Endocrine;Genitourinary; Neurologic

Intervention: Endocrine

Rationale: Individuals can demonstrate a number of endocrine deficiencies (including central hypothyroidism, as well as growth hormone deficiency), for which hormone replacement therapy may be beneficial

Refs: 23143598

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to IGSF1 variants in ClinVar

10 Conditions Cataloged

Inborn genetic diseasesTotal: 148

not providedTotal: 87

X-linked central congenital hypothyroidism with late-onset testicular enlargementTotal: 36

not specifiedTotal: 31

IGSF1-related disorderTotal: 21

Pituitary hormone deficiencyTotal: 2

Congenital hypogonadotropic hypogonadismTotal: 2

IGSF1-related disordersTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001555.5. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			32 clinvar	25 clinvar	5 clinvar	62
missense	3 clinvar		250 clinvar	52 clinvar	7 clinvar	312
nonsense	10 clinvar	5 clinvar	19 clinvar			34
start loss						0
frameshift	9 clinvar	3 clinvar	1 clinvar			13
splice donor/acceptor (+/-2bp)	2 clinvar	3 clinvar	38 clinvar			43
Total	24	11	340	77	12	464

Highest pathogenic variant AF is 0.00002486183

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 40 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001555.5	RefSeq	NP_001546.2	19	MANE Select
ENST00000361420.8	Ensembl	ENSP00000355010.3	19	MANE Select
NM_001170961.2	RefSeq	NP_001164432.1	19	Standard
NM_001170962.2	RefSeq	NP_001164433.1	18	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

regulation of transcription, DNA-templated
negative regulation of activin receptor signaling pathway

Molecular Function

protein binding
coreceptor activity
inhibin binding
activin receptor antagonist activity

Cellular Component

extracellular region
membrane
integral component of membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000370903
Coding exons: 19
Length: 126198
Individuals with no LoFs: 125737
Homozygous LoFs: 2
Heterozygous LoFs: 7
Defined: 125746
p: 0.0000358

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.15	439	512	0.857	0.0000376	8727
Missense (PolyPhen)		126	193.52	0.65108		3583
Synonymous	-1.05	213	194	1.10	0.0000146	2677
Loss of Function	5.83	5	49.1	0.102	0.00000388	732

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0.00013	0.000099	rare
East Asian	0	0.0	absent
Finnish	0.00013	0.000092	rare
European (Non-Finnish)	0.000061	0.000044	rare
South Asian	0.000053	0.000033	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: 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 (By similarity). Necessary to mediate a specific antagonistic effect of inhibin B on activin-stimulated transcription. {ECO:0000250, ECO:0000269|PubMed:11266516}.;
Disease: DISEASE: 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. {ECO:0000269|PubMed:23143598}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.109

Intolerance Scores

LoFtool: 0.379
RVIS EVS: -0.62
RVIS percentile EVS: 17.47

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.517

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium