GFRA1
protein-codingGDNF family receptor alpha 1
Gene summary
This gene encodes a member of the glial cell line-derived neurotrophic factor receptor (GDNFR) family of proteins. The encoded preproprotein is proteolytically processed to generate the mature receptor. Glial cell line-derived neurotrophic factor (GDNF) and neurturin (NTN) are two structurally related, potent neurotrophic factors that play key roles in the control of neuron survival and differentiation. This receptor is a glycosylphosphatidylinositol (GPI)-linked cell surface receptor for both GDNF and NTN, and mediates activation of the RET tyrosine kinase receptor. This gene is a candidate gene for Hirschsprung disease. Alternative splicing results in multiple transcript variants, at least one of which encodes a preproprotein that is proteolytically processed. [provided by RefSeq, Jan 2016]
- GDNFRA
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~219.9 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0030822
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0030822
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0030822
Submitter: Ambry Genetics
Clinical Genomic Database (CGD)
Manifestation: Genitourinary; Renal
Intervention: General
Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to GFRA1 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_005264.8. 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 | 10 | 2 | 12 | |||
| missense | 53 | 3 | 1 | 57 | ||
| nonsense | 1 | 1 | 2 | |||
| start loss | 1 | 1 | ||||
| frameshift | 2 | 2 | ||||
| splice donor/acceptor (+/-2bp) | 0 | |||||
| Total | 3 | 1 | 54 | 13 | 3 | 74 |
Highest pathogenic variant AF is 0.000013151352
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_005255.1 | 10 | MANE Select | |
| Ensembl | ENSP00000347591.6 | 10 | MANE Select | |
| RefSeq | NP_001138925.1 | 9 | Standard | |
| RefSeq | NP_001335025.1 | 9 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| gfra1a | Danio rerio | Structure: enteric neuron Quality: decreased amount abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Exercise-induced Circadian Regulation
- Developmental Biology
- Signal Transduction
- IL-7 signaling
- RAF/MAP kinase cascade
Biological Process
- MAPK cascade
- cell surface receptor signaling pathway
- nervous system development
- axon guidance
- glial cell-derived neurotrophic factor receptor signaling pathway
Molecular Function
- Ras guanyl-nucleotide exchange factor activity
- signaling receptor binding
- glial cell-derived neurotrophic factor receptor activity
Cellular Component
- plasma membrane
- external side of plasma membrane
- extrinsic component of membrane
- anchored component of membrane
- receptor complex
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000355422
- Coding exons
- 10
- Length
- 216536
- Individuals with no LoFs
- 125737
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 11
- Defined
- 125748
- p
- 0.0000437
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 1.39 | 214 | 280 | 0.766 | 0.0000158 | 3046 |
| Missense (PolyPhen) | 48 | 84.405 | 0.56868 | 917 | ||
| Synonymous | -0.967 | 133 | 120 | 1.11 | 0.00000737 | 895 |
| Loss of Function | 3.24 | 6 | 22.6 | 0.265 | 0.00000104 | 270 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00012 | 0.00012 | rare |
| Latino/Admixed American | 0.000058 | 0.000058 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.000054 | 0.000054 | rare |
| Finnish | 0.000046 | 0.000046 | rare |
| European (Non-Finnish) | 0.000044 | 0.000044 | rare |
| South Asian | 0 | 0.0 | absent |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Receptor for GDNF. Mediates the GDNF-induced autophosphorylation and activation of the RET receptor (By similarity). {ECO:0000250}.;
Recessive Scores
- pRec
- 0.184
Intolerance Scores
- LoFtool
- 0.565
- RVIS EVS
- -0.29
- RVIS percentile EVS
- 33.34
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.510
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |