IGSF1

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

Basic information

Region (hg38): X:131273505-131578899

Links

ENSG00000147255 ∙ NCBI:3547 ∙ OMIM:300137 ∙ HGNC:5948 ∙ Uniprot:Q8N6C5 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• X-linked central congenital hypothyroidism with late-onset testicular enlargement (Definitive), mode of inheritance: XLR
• X-linked central congenital hypothyroidism with late-onset testicular enlargement (Definitive), mode of inheritance: XL
• X-linked central congenital hypothyroidism with late-onset testicular enlargement (Strong), mode of inheritance: XL
• X-linked central congenital hypothyroidism with late-onset testicular enlargement (Supportive), mode of inheritance: XL
• X-linked central congenital hypothyroidism with late-onset testicular enlargement (Definitive), mode of inheritance: XL

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Central hypothyroidism and testicular enlargement	XL	Endocrine	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	Endocrine;Genitourinary; Neurologic	23143598

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the IGSF1 gene.

• not provided (67 variants)
• Inborn genetic diseases (48 variants)
• X-linked central congenital hypothyroidism with late-onset testicular enlargement (20 variants)
• not specified (12 variants)
• Hypothyroidism due to TSH receptor mutations (1 variants)
• IGSF1-related condition (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the IGSF1 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			1	5	9	15
missense			48	23	5	76
nonsense	4	2	1			7
start loss						0
frameshift		1	1			2
inframe indel			2			2
splice donor/acceptor (+/-2bp)	2	1				3
splice region				2	2	4
non coding			1		14	15
Total	6	4	54	28	28

Variants in IGSF1

This is a list of pathogenic ClinVar variants found in the IGSF1 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
X-131273818-A-G		Inborn genetic diseases	Likely benign (Dec 07, 2023)
X-131273852-T-A			Uncertain significance (Oct 23, 2019)
X-131273860-G-A		Inborn genetic diseases	Uncertain significance (Dec 06, 2022)
X-131273872-C-T		Inborn genetic diseases	Uncertain significance (Aug 03, 2022)
X-131273901-G-C		not specified	Benign (-)
X-131273918-CTG-C			Uncertain significance (Feb 28, 2017)
X-131274112-C-G		Inborn genetic diseases	Likely benign (Nov 27, 2023)
X-131274145-A-C		X-linked central congenital hypothyroidism with late-onset testicular enlargement	Uncertain significance (Apr 01, 2020)
X-131274153-C-G			Uncertain significance (Jan 04, 2022)
X-131274168-G-A		X-linked central congenital hypothyroidism with late-onset testicular enlargement	Pathogenic (Jul 07, 2020)
X-131274195-G-A			Pathogenic (Jul 01, 2023)
X-131274198-C-T		Inborn genetic diseases • IGSF1-related disorder	Likely benign (May 18, 2023)
X-131274457-T-C			Benign (Nov 12, 2018)
X-131274681-G-C		X-linked central congenital hypothyroidism with late-onset testicular enlargement	Uncertain significance (Mar 25, 2024)
X-131274688-A-G			Uncertain significance (Mar 08, 2017)
X-131274722-C-A			Uncertain significance (May 23, 2022)
X-131274763-T-C			Likely benign (Mar 01, 2024)
X-131274768-T-TA		X-linked central congenital hypothyroidism with late-onset testicular enlargement	Pathogenic (Dec 01, 2012)
X-131274771-G-A		not specified • X-linked central congenital hypothyroidism with late-onset testicular enlargement	Benign (Aug 10, 2021)
X-131274799-C-T		IGSF1-related disorder	Benign (Apr 16, 2019)
X-131274800-G-A		X-linked central congenital hypothyroidism with late-onset testicular enlargement	Pathogenic (Sep 08, 2021)
X-131275004-A-T		X-linked central congenital hypothyroidism with late-onset testicular enlargement	Uncertain significance (May 22, 2022)
X-131275095-C-T		IGSF1-related disorder	Benign (Dec 31, 2019)
X-131275097-C-G		Inborn genetic diseases	Uncertain significance (Sep 29, 2022)
X-131275138-C-A		Inborn genetic diseases	Likely benign (May 09, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
IGSF1	protein_coding	protein_coding	ENST00000370903	19	126198

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.00	0.0000726	125737	2	7	125746	0.0000358

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.15	439	512	0.857	0.0000376	8727
Missense in 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

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00	0.00
Ashkenazi Jewish	0.000134	0.0000992
East Asian	0.00	0.00
Finnish	0.000125	0.0000924
European (Non-Finnish)	0.0000614	0.0000439
Middle Eastern	0.00	0.00
South Asian	0.0000530	0.0000327
Other	0.00	0.00

dbNSFP

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

Haploinsufficiency Scores

• pHI: 0.603
• hipred: Y
• hipred_score: 0.536
• ghis: 0.527

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.517

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Igsf1
• Phenotype: nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); normal phenotype; homeostasis/metabolism phenotype; endocrine/exocrine gland phenotype; growth/size/body region phenotype

Gene ontology

• Biological process: regulation of transcription, DNA-templated;negative regulation of activin receptor signaling pathway
• Cellular component: extracellular region;membrane;integral component of membrane
• Molecular function: protein binding;coreceptor activity;inhibin binding;activin receptor antagonist activity