NRG3
protein-codingneuregulin 3, the group of Neuregulins
Gene summary
This gene is a member of the neuregulin gene family. This gene family encodes ligands for the transmembrane tyrosine kinase receptors ERBB3 and ERBB4 - members of the epidermal growth factor receptor family. Ligand binding activates intracellular signaling cascades and the induction of cellular responses including proliferation, migration, differentiation, and survival or apoptosis. This gene encodes neuregulin 3 (NRG3). NRG3 has been shown to activate the tyrosine phosphorylation of its cognate receptor, ERBB4, and is thought to influence neuroblast proliferation, migration and differentiation by signalling through ERBB4. NRG3 also promotes mammary differentiation during embryogenesis. Linkage studies have implicated this gene as a susceptibility locus for schizophrenia and schizoaffective disorder. Alternative splicing results in multiple transcript variants encoding distinct isoforms. Additional transcript variants have been described but their biological validity has not been verified.[provided by RefSeq, Sep 2009]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~1,112.0 kbGenCC 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 NRG3 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_001010848.4. 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 | 4 | 5 | |||
| missense | 100 | 3 | 2 | 105 | ||
| nonsense | 0 | |||||
| start loss | 0 | |||||
| frameshift | 0 | |||||
| splice donor/acceptor (+/-2bp) | 1 | 1 | ||||
| Total | 0 | 0 | 101 | 4 | 6 | 111 |
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_001010848.2 | 9 | MANE Select | |
| Ensembl | ENSP00000361214.2 | 9 | MANE Select | |
| RefSeq | NP_001159444.1 | 9 | Standard | |
| RefSeq | NP_001159445.1 | 11 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- ErbB signaling pathway - Homo sapiens (human)
- EGFR Inhibitor Pathway, Pharmacodynamics
- EGF-Core
- ErbB Signaling Pathway
- SHC1 events in ERBB2 signaling
Biological Process
- regulation of cell growth
- activation of transmembrane receptor protein tyrosine kinase activity
- pattern specification process
- regulation of signaling receptor activity
- chemorepulsion involved in interneuron migration from the subpallium to the cortex
Molecular Function
- signaling receptor binding
- growth factor activity
- transmembrane receptor protein tyrosine kinase activator activity
- receptor tyrosine kinase binding
- chemorepellent activity
Cellular Component
- extracellular region
- extracellular space
- integral component of plasma membrane
- glutamatergic synapse
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000372141
- Coding exons
- 9
- Length
- 1111866
- Individuals with no LoFs
- 125677
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 71
- Defined
- 125748
- p
- 0.000282
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | -0.257 | 385 | 371 | 1.04 | 0.0000187 | 4473 |
| Missense (PolyPhen) | 124 | 152.48 | 0.81323 | 1770 | ||
| Synonymous | -1.04 | 171 | 155 | 1.11 | 0.00000833 | 1464 |
| Loss of Function | 3.85 | 8 | 31.2 | 0.256 | 0.00000189 | 329 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00031 | 0.00031 | rare |
| Latino/Admixed American | 0.000029 | 0.000029 | rare |
| Ashkenazi Jewish | 0.0020 | 0.0020 | notable |
| East Asian | 0.00016 | 0.00016 | rare |
| Finnish | 0.00014 | 0.00014 | rare |
| European (Non-Finnish) | 0.00025 | 0.00025 | rare |
| South Asian | 0.00026 | 0.00026 | rare |
| Other | 0.00049 | 0.00049 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Direct ligand for the ERBB4 tyrosine kinase receptor. Binding results in ligand-stimulated tyrosine phosphorylation and activation of the receptor. Does not bind to the EGF receptor, ERBB2 or ERBB3 receptors. May be a survival factor for oligodendrocytes. {ECO:0000269|PubMed:16478787, ECO:0000269|PubMed:9275162}.;
Recessive Scores
- pRec
- 0.103
Intolerance Scores
- LoFtool
- 0.580
- RVIS EVS
- -0.46
- RVIS percentile EVS
- 23.57
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.639
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |