IRS4
protein-codinginsulin receptor substrate 4
Gene summary
IRS4 encodes the insulin receptor substrate 4, a cytoplasmic protein that contains many potential tyrosine and serine/threonine phosphorylation sites. Tyrosine-phosphorylated IRS4 protein has been shown to associate with cytoplasmic signalling molecules that contain SH2 domains. The IRS4 protein is phosphorylated by the insulin receptor tyrosine kinase upon receptor stimulation.. [provided by RefSeq, Jul 2008]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~16.6 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: XL
Disease ID:MONDO:0026732
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: XL
Disease ID:MONDO:0026732
Submitter: Ambry Genetics
Inheritance Pattern: XL
Disease ID:MONDO:0026732
Submitter: PanelApp Australia
Clinical Genomic Database (CGD)
Manifestation: Endocrine
Intervention: Endocrine
Rationale: The condition can manifest with early clinical signs, of hypothyroidism, and treatment with thyroid hormone replacement has been reported
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to IRS4 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_001379150.1. 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 | 13 | 2 | 15 | |||
| missense | 134 | 15 | 3 | 152 | ||
| nonsense | 2 | 2 | ||||
| start loss | 0 | |||||
| frameshift | 1 | 1 | 2 | 4 | ||
| splice donor/acceptor (+/-2bp) | 0 | |||||
| Total | 1 | 3 | 136 | 28 | 5 | 173 |
Highest pathogenic variant AF is 0.000039785722
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_001366079.1 | 2 | MANE Select | |
| Ensembl | ENSP00000361202.3 | 2 | MANE Select | |
| RefSeq | NP_001427746.1 | 3 | Standard | |
| RefSeq | NP_003595.1 | 1 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- 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)
Biological Process
- signal transduction
- insulin receptor signaling pathway
- positive regulation of signal transduction
Molecular Function
- SH3/SH2 adaptor activity
- insulin receptor binding
- protein binding
- phosphatidylinositol 3-kinase binding
Cellular Component
- cytosol
- plasma membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000372129
- Coding exons
- 1
- Length
- 3940
- Individuals with no LoFs
- 0
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 0
- Defined
- 0
- p
- 0.00
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.0893 | 485 | 491 | 0.989 | 0.0000351 | 8088 |
| Missense (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 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0 | 0.0 | absent |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0 | 0.0 | absent |
| South Asian | 0 | 0.0 | absent |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- 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}.;
Recessive Scores
- pRec
- 0.209
Intolerance Scores
- LoFtool
- 0.163
- RVIS EVS
- 0.54
- RVIS percentile EVS
- 81.07
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.914
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |