IRS1

protein-coding

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

Gene summary

This gene encodes a protein which is phosphorylated by insulin receptor tyrosine kinase. Mutations in this gene are associated with type II diabetes and susceptibility to insulin resistance. [provided by RefSeq, Nov 2009]

MANE transcript

NM_005544.3

Inheritance

—

ClinVar variants

P:1U:172B:49

Top phenotype

IRS1-related disorder

gnomAD constraint

pLI —, LoF o/e 0.29

Max pathogenic AF

—

Genomic locus

chr2:226,731,312-226,799,820

External References & Databases

Ensembl (ENSG00000169047)

Transcript & Mutation Effects

hg38 • Region Span ~68.5 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

No GenCC data available for this gene.

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to IRS1 variants in ClinVar

5 Conditions Cataloged

not specifiedTotal: 197

not providedTotal: 29

IRS1-related disorderTotal: 11

Type 2 diabetes mellitusTotal: 7

Periventricular heterotopia with microcephaly, autosomal recessiveTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_005544.3. 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			1 clinvar	31 clinvar	5 clinvar	37
missense	1 clinvar		171 clinvar	11 clinvar	2 clinvar	185
nonsense						0
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)						0
Total	1	0	172	42	7	222

Highest pathogenic variant AF is 0.000021068652

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 7 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_005544.3	RefSeq	NP_005535.1	1	MANE Select
ENST00000305123.6	Ensembl	ENSP00000304895.4	1	MANE Select
ENST00000918829.1	Ensembl	ENSP00000588888.1	1	Standard
ENST00000918829.2	Ensembl	ENSP00000588888.1	1	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

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)

Biological Process

MAPK cascade
signal transduction
positive regulation of cell population proliferation
insulin receptor signaling pathway
positive regulation of glucose metabolic process

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

Cellular Component

nucleus
cytoplasm
cytosol
plasma membrane
insulin receptor complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000305123
Coding exons: 1
Length: 68443
Individuals with no LoFs: 125729
Homozygous LoFs: 0
Heterozygous LoFs: 19
Defined: 125748
p: 0.0000756

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.0676	787	792	0.993	0.0000512	8068
Missense (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

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000058	0.000058	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00011	0.00011	rare
Finnish	0.00014	0.00014	rare
European (Non-Finnish)	0.000080	0.000079	rare
South Asian	0.000033	0.000033	rare
Other	0.00033	0.00033	rare

dbNSFP Gene Annotations

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.;

Recessive Scores

pRec: 0.811

Intolerance Scores

LoFtool: 0.354
RVIS EVS: -1.3
RVIS percentile EVS: 4.97

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.989

Gene Damage Prediction

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