IRS4

insulin receptor substrate 4

Basic information

Region (hg38): X:108719945-108736563

Links

ENSG00000133124 ∙ NCBI:8471 ∙ OMIM:300904 ∙ HGNC:6128 ∙ Uniprot:O14654 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• hypothyroidism, congenital, nongoitrous, 9 (Limited), mode of inheritance: XL
• hypothyroidism, congenital, nongoitrous, 9 (Strong), mode of inheritance: XL

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Hypothyroidism, congenital, nongoitrous, 9	XL	Endocrine	The condition can manifest with early clinical signs, of hypothyroidism, and treatment with thyroid hormone replacement has been reported	Endocrine	30061370

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the IRS4 gene.

• Inborn genetic diseases (50 variants)
• not provided (23 variants)
• Hypothyroidism, congenital, nongoitrous, 9 (5 variants)
• not specified (2 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the IRS4 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				5	3	8
missense			51	7	4	62
nonsense		2				2
start loss						0
frameshift		1	1			2
inframe indel						0
splice donor/acceptor (+/-2bp)						0
splice region					1	1
non coding						0
Total	0	3	52	12	7

Variants in IRS4

This is a list of pathogenic ClinVar variants found in the IRS4 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-108732576-G-T			Benign (Dec 31, 2019)
X-108732617-A-C			Uncertain significance (Jan 08, 2022)
X-108732657-C-A		not specified	Benign (Dec 31, 2019)
X-108732669-G-T		not specified	Uncertain significance (Aug 17, 2022)
X-108732693-G-C		not specified	Uncertain significance (Sep 26, 2023)
X-108732721-A-C			Likely benign (Dec 01, 2022)
X-108732755-G-A		not specified	Uncertain significance (Jun 29, 2023)
X-108732809-T-C		not specified	Uncertain significance (Dec 17, 2023)
X-108732811-G-T			Likely benign (Mar 01, 2023)
X-108732828-C-T		not specified	Uncertain significance (Jun 29, 2023)
X-108732873-C-T			Benign (Dec 31, 2019)
X-108732928-C-A			Likely benign (Apr 01, 2022)
X-108733023-G-C		not specified	Uncertain significance (Jul 14, 2023)
X-108733045-G-C			Likely benign (Jan 01, 2023)
X-108733130-G-A		Hypothyroidism, congenital, nongoitrous, 9	Uncertain significance (Feb 28, 2020)
X-108733179-TACAGC-T		Hypothyroidism, congenital, nongoitrous, 9	Pathogenic (Sep 26, 2019)
X-108733240-G-A			Benign (Dec 31, 2019)
X-108733293-C-A			Likely pathogenic (Jun 12, 2021)
X-108733305-C-T		not specified	Uncertain significance (Jun 13, 2023)
X-108733320-C-A		IRS4-related disorder	Likely benign (Oct 26, 2020)
X-108733344-G-A		not specified	Uncertain significance (Jan 11, 2023)
X-108733461-C-T		not specified	Uncertain significance (Apr 18, 2023)
X-108733493-G-A			Likely benign (Nov 01, 2023)
X-108733631-G-A		not specified	Uncertain significance (Apr 18, 2023)
X-108733652-C-T		not specified	Uncertain significance (Dec 07, 2021)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
IRS4	protein_coding	protein_coding	ENST00000372129	1	3940

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.578	0.422	0	0	0	0	0.00

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.0893	485	491	0.989	0.0000351	8088
Missense in Polyphen		66	98.241	0.67182		1618
Synonymous	-3.56	262	198	1.32	0.0000146	2738
Loss of Function	3.64	5	24.4	0.205	0.00000190	429

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00	0.00
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.00	0.00
European (Non-Finnish)	0.00	0.00
Middle Eastern	0.00	0.00
South Asian	0.00	0.00
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Acts as an interface between multiple growth factor receptors possessing tyrosine kinase activity, such as insulin receptor, IGF1R and FGFR1, and a complex network of intracellular signaling molecules containing SH2 domains. Involved in the IGF1R mitogenic signaling pathway. Promotes the AKT1 signaling pathway and BAD phosphorylation during insulin stimulation without activation of RPS6KB1 or the inhibition of apoptosis. Interaction with GRB2 enhances insulin-stimulated mitogen-activated protein kinase activity. May be involved in nonreceptor tyrosine kinase signaling in myoblasts. Plays a pivotal role in the proliferation/differentiation of hepatoblastoma cell through EPHB2 activation upon IGF1 stimulation. May play a role in the signal transduction in response to insulin and to a lesser extent in response to IL4 and GH on mitogenesis. Plays a role in growth, reproduction and glucose homeostasis. May act as negative regulators of the IGF1 signaling pathway by suppressing the function of IRS1 and IRS2. {ECO:0000269|PubMed:10531310, ECO:0000269|PubMed:10594015, ECO:0000269|PubMed:12639902, ECO:0000269|PubMed:17408801, ECO:0000269|PubMed:9553137}.
• Pathway: Regulation of lipolysis in adipocytes - Homo sapiens (human);Adipocytokine signaling pathway - Homo sapiens (human);Type II diabetes mellitus - Homo sapiens (human);Longevity regulating pathway - multiple species - Homo sapiens (human);Autophagy - animal - Homo sapiens (human);FoxO signaling pathway - Homo sapiens (human);AMPK signaling pathway - Homo sapiens (human);Longevity regulating pathway - Homo sapiens (human);cGMP-PKG signaling pathway - Homo sapiens (human);Insulin signaling pathway - Homo sapiens (human);EGF-Core;IGF-Core;Adipogenesis;Angiopoietin Like Protein 8 Regulatory Pathway;Focal Adhesion-PI3K-Akt-mTOR-signaling pathway;Leptin Insulin Overlap;Insulin Signaling;Signal Transduction;insulin Mam;Leptin;IRS-related events triggered by IGF1R;IGF1R signaling cascade;Signaling by Receptor Tyrosine Kinases;Signaling by Type 1 Insulin-like Growth Factor 1 Receptor (IGF1R);insulin (Consensus)

Recessive Scores

• pRec: 0.209

Intolerance Scores

• loftool: 0.163
• rvis_EVS: 0.54
• rvis_percentile_EVS: 81.07

Haploinsufficiency Scores

• pHI: 0.0550
• hipred: Y
• hipred_score: 0.597

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.914

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Irs4
• Phenotype: reproductive system phenotype; liver/biliary system phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); adipose tissue phenotype (the observable morphological and physiological characteristics of mammalian fat tissue that are manifested through development and lifespan); growth/size/body region phenotype; homeostasis/metabolism phenotype

Gene ontology

• Biological process: signal transduction;insulin receptor signaling pathway;positive regulation of signal transduction
• Cellular component: cytosol;plasma membrane
• Molecular function: SH3/SH2 adaptor activity;insulin receptor binding;protein binding;phosphatidylinositol 3-kinase binding