IRS1

insulin receptor substrate 1, the group of Pleckstrin homology domain containing

Basic information

Region (hg38): 2:226731311-226799820

Links

ENSG00000169047 ∙ NCBI:3667 ∙ OMIM:147545 ∙ HGNC:6125 ∙ Uniprot:P35568 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

No genCC data.

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the IRS1 gene.

• Inborn genetic diseases (45 variants)
• not provided (20 variants)
• Type 2 diabetes mellitus (5 variants)
• not specified (2 variants)
• Hypotrichosis 13;Type 2 diabetes mellitus;Wooly hair, autosomal recessive 3 (1 variants)
• IRS1-related condition (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the IRS1 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				7	8	15
missense			47	2	3	52
nonsense		1				1
start loss						0
frameshift						0
inframe indel				1		1
splice donor/acceptor (+/-2bp)						0
splice region						0
non coding						0
Total	0	1	47	10	11

Variants in IRS1

This is a list of pathogenic ClinVar variants found in the IRS1 region.

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

Position	Type	Phenotype	Significance	ClinVar
2-226795035-T-C		not specified	Uncertain significance (Aug 10, 2021)
2-226795099-C-G		not specified	Uncertain significance (Aug 16, 2021)
2-226795104-C-T		IRS1-related disorder	Uncertain significance (Mar 01, 2023)
2-226795160-C-T			Benign (Jun 14, 2018)
2-226795224-C-A		not specified	Uncertain significance (Oct 18, 2021)
2-226795250-T-G			Benign (Dec 31, 2019)
2-226795330-C-T			Benign (Dec 31, 2019)
2-226795333-C-T		IRS1-related disorder	Likely benign (Mar 10, 2022)
2-226795363-C-G		not specified	Uncertain significance (Dec 27, 2023)
2-226795374-C-A		not specified	Uncertain significance (Sep 14, 2022)
2-226795377-G-A		not specified	Uncertain significance (Jan 25, 2023)
2-226795389-A-C		not specified	Uncertain significance (Jan 09, 2024)
2-226795417-G-C		not specified	Uncertain significance (Aug 17, 2021)
2-226795453-G-C		not specified	Uncertain significance (Jan 17, 2023)
2-226795474-G-A		not specified	Uncertain significance (Dec 21, 2022)
2-226795498-G-A		not specified	Uncertain significance (Jul 12, 2023)
2-226795504-G-A		Type 2 diabetes mellitus	Uncertain significance (Mar 18, 2016)
2-226795569-G-A		not specified	Uncertain significance (Feb 07, 2023)
2-226795608-G-A		not specified	Uncertain significance (May 09, 2023)
2-226795660-G-A		not specified	Uncertain significance (May 06, 2022)
2-226795720-C-T		not specified	Uncertain significance (Nov 17, 2023)
2-226795725-G-A		not specified	Uncertain significance (May 04, 2022)
2-226795731-T-G		not specified	Uncertain significance (Dec 22, 2023)
2-226795800-C-T		not specified	Uncertain significance (Aug 02, 2021)
2-226795828-C-T		Insulin resistance, susceptibility to • Coronary artery disease, susceptibility to	risk factor (Jul 01, 2004)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
IRS1	protein_coding	protein_coding	ENST00000305123	1	68443

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.0236	0.976	125729	0	19	125748	0.0000756

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.0676	787	792	0.993	0.0000512	8068
Missense in Polyphen		297	334.36	0.88826		3349
Synonymous	0.122	323	326	0.991	0.0000218	2678
Loss of Function	3.69	9	31.3	0.288	0.00000205	326

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.0000578	0.0000578
Ashkenazi Jewish	0.00	0.00
East Asian	0.000109	0.000109
Finnish	0.000139	0.000139
European (Non-Finnish)	0.0000797	0.0000791
Middle Eastern	0.000109	0.000109
South Asian	0.0000327	0.0000327
Other	0.000326	0.000326

dbNSFP

Source: dbNSFP

• Function: FUNCTION: May mediate the control of various cellular processes by insulin. When phosphorylated by the insulin receptor binds specifically to various cellular proteins containing SH2 domains such as phosphatidylinositol 3-kinase p85 subunit or GRB2. Activates phosphatidylinositol 3-kinase when bound to the regulatory p85 subunit (By similarity). {ECO:0000250, ECO:0000269|PubMed:16878150}.
• Disease: DISEASE: Diabetes mellitus, non-insulin-dependent (NIDDM) [MIM:125853]: A multifactorial disorder of glucose homeostasis caused by a lack of sensitivity to the body's own insulin. Affected individuals usually have an obese body habitus and manifestations of a metabolic syndrome characterized by diabetes, insulin resistance, hypertension and hypertriglyceridemia. The disease results in long-term complications that affect the eyes, kidneys, nerves, and blood vessels. {ECO:0000269|PubMed:10206679, ECO:0000269|PubMed:12843189, ECO:0000269|PubMed:8723689}. Note=The gene represented in this entry may be involved in disease pathogenesis.
• Pathway: PI3K-Akt signaling pathway - Homo sapiens (human);mTOR signaling pathway - Homo sapiens (human);Regulation of lipolysis in adipocytes - Homo sapiens (human);Adipocytokine signaling pathway - Homo sapiens (human);Neurotrophin signaling pathway - Homo sapiens (human);Type II diabetes mellitus - Homo sapiens (human);Insulin resistance - Homo sapiens (human);Non-alcoholic fatty liver disease (NAFLD) - 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);Aldosterone-regulated sodium reabsorption - Homo sapiens (human);MicroRNAs in cancer - Homo sapiens (human);cGMP-PKG signaling pathway - Homo sapiens (human);Insulin signaling pathway - Homo sapiens (human);Anti-diabetic Drug Potassium Channel Inhibitors Pathway, Pharmacodynamics;Leucine Stimulation on Insulin Signaling;Insulin Signalling;EGF-Core;IGF-Core;JAK-STAT-Core;Type II diabetes mellitus;Integrated Breast Cancer Pathway;miR-targeted genes in lymphocytes - TarBase;miR-targeted genes in muscle cell - TarBase;Leptin signaling pathway;Prolactin Signaling Pathway;Signaling Pathways in Glioblastoma;AGE-RAGE pathway;Adipogenesis;Oncostatin M Signaling Pathway;Brain-Derived Neurotrophic Factor (BDNF) signaling pathway;Alpha 6 Beta 4 signaling pathway;Integrated Lung Cancer Pathway;JAK-STAT;Transcription factor regulation in adipogenesis;Factors and pathways affecting insulin-like growth factor (IGF1)-Akt signaling;IL-4 Signaling Pathway;Angiopoietin Like Protein 8 Regulatory Pathway;Focal Adhesion-PI3K-Akt-mTOR-signaling pathway;Leptin Insulin Overlap;PI3K-Akt Signaling Pathway;Insulin Signaling;EPO Receptor Signaling;Interferon type I signaling pathways;DNA Damage Response (only ATM dependent);Disease;Signal Transduction;mtor signaling pathway;regulation of eif-4e and p70s6 kinase;Growth hormone receptor signaling;il-2 receptor beta chain in t cell activation;multiple antiapoptotic pathways from igf-1r signaling lead to bad phosphorylation;insulin signaling pathway;Cytokine Signaling in Immune system;Alpha6Beta4Integrin;IRS activation;Signal attenuation;PI3K Cascade;SOS-mediated signalling;IRS-mediated signalling;Insulin receptor signalling cascade;Signaling by Insulin receptor;igf-1 signaling pathway;Oncostatin_M;IGF signaling;Immune System;Ghrelin;insulin Mam;Signaling by NTRK1 (TRKA);Signaling by NTRKs;BDNF;SHP2 signaling;growth hormone signaling pathway;the igf-1 receptor and longevity;PI3K/AKT activation;RAF/MAP kinase cascade;MAPK1/MAPK3 signaling;MAPK family signaling cascades;PIP3 activates AKT signaling;IL2;Signaling by Leptin;Signaling events regulated by Ret tyrosine kinase;IL2-mediated signaling events;PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling;Negative regulation of the PI3K/AKT network;IL4;Leptin;Constitutive Signaling by Aberrant PI3K in Cancer;PI3K/AKT Signaling in Cancer;IRS-related events triggered by IGF1R;IGF1R signaling cascade;TNFalpha;IL-7;Signaling by Receptor Tyrosine Kinases;Intracellular signaling by second messengers;mTOR signaling pathway;Insulin Pathway;Diseases of signal transduction;IGF1 pathway;IL4-mediated signaling events;Signaling events mediated by PTP1B;Signaling by Type 1 Insulin-like Growth Factor 1 Receptor (IGF1R);Integrins in angiogenesis;S1P2 pathway;IL-13 signaling;insulin (Consensus)

Recessive Scores

• pRec: 0.811

Intolerance Scores

• loftool: 0.354
• rvis_EVS: -1.3
• rvis_percentile_EVS: 4.97

Haploinsufficiency Scores

• pHI: 0.945
• hipred: Y
• hipred_score: 0.765
• ghis: 0.541

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.989

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Irs1
• Phenotype: skeleton phenotype; immune system phenotype; hearing/vestibular/ear phenotype; limbs/digits/tail phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); hematopoietic system phenotype; cellular phenotype; homeostasis/metabolism phenotype; muscle phenotype; adipose tissue phenotype (the observable morphological and physiological characteristics of mammalian fat tissue that are manifested through development and lifespan); endocrine/exocrine gland phenotype; growth/size/body region phenotype

Gene ontology

• Biological process: MAPK cascade;signal transduction;positive regulation of cell population proliferation;insulin receptor signaling pathway;positive regulation of glucose metabolic process;phosphatidylinositol 3-kinase signaling;positive regulation of fatty acid beta-oxidation;response to insulin;cellular response to insulin stimulus;phosphatidylinositol-3-phosphate biosynthetic process;interleukin-7-mediated signaling pathway;glucose homeostasis;response to peptide hormone;positive regulation of phosphatidylinositol 3-kinase activity;positive regulation of glycogen biosynthetic process;positive regulation of glucose import;negative regulation of insulin receptor signaling pathway;positive regulation of insulin receptor signaling pathway;negative regulation of insulin secretion;phosphatidylinositol phosphorylation;insulin-like growth factor receptor signaling pathway;phosphatidylinositol-mediated signaling;positive regulation of protein kinase B signaling
• Cellular component: nucleus;cytoplasm;cytosol;plasma membrane;insulin receptor complex;caveola;intracellular membrane-bounded organelle
• Molecular function: phosphotyrosine residue binding;transmembrane receptor protein tyrosine kinase adaptor activity;SH3/SH2 adaptor activity;protein kinase C binding;Ras guanyl-nucleotide exchange factor activity;insulin receptor binding;insulin-like growth factor receptor binding;protein binding;1-phosphatidylinositol-3-kinase activity;SH2 domain binding;phosphatidylinositol 3-kinase binding;phosphatidylinositol-4,5-bisphosphate 3-kinase activity