GRAP
protein-codingGRB2 related adaptor protein, the group of SH2 domain containing
Gene summary
This gene encodes a member of the GRB2/Sem5/Drk family and functions as a cytoplasmic signaling protein which contains an SH2 domain flanked by two SH3 domains. The SH2 domain interacts with ligand-activated receptors for stem cell factor and erythropoietin, and facilitates the formation of a stable complex with the BCR-ABL oncoprotein. This protein also associates with the Ras guanine nucleotide exchange factor SOS1 (son of sevenless homolog 1) through its N-terminal SH3 domain. In general, it couples signals from receptor and cytoplasmic tyrosine kinases to the Ras signaling pathway. [provided by RefSeq, Jul 2012]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~26.4 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0019588
Submitter: Orphanet
Inheritance Pattern: Unknown
Disease ID:MONDO:0032761
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0032761
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0019497
Submitter: ClinGen
GRAP was first reported in relation to autosomal recessive nonsyndromic hearing loss (DFNB114) in 2019 (Li et al., PMID:30610177). One missense variant (c.311A>T, p.Gln104Leu) that has been reported in 4 individuals from 2 unrelated families in 1 publication is included in this curation (PMID:30610177). The mechanism of pathogenicity is unclear. This gene-disease relationship is also supported by expression data demonstrating that GRAP is localized in the spiral ganglion neuron fibers, inner and outer innervating auditory hair cells, and the utricular hair cells (PMID: 30610177). An animal model also suggests that this gene can cause functional and morphological abnormalities of the scolopidia and sensory neurons in compound heterozygous (drk6/drk14−7 and drk6/drke0A) and mosaic (eyFLP; drkΔ) Drosophila (PMID: 30610177). In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship.
Clinical Genomic Database (CGD)
Manifestation: Audiologic/Otolaryngologic
Intervention: Audiologic/Otolaryngologic
Rationale: Early recognition and treatment of hearing impairment may improve outcomes, including speech and language development
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to GRAP variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_006613.4. 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 | 4 | 4 | ||||
| missense | 1 | 17 | 18 | |||
| nonsense | 0 | |||||
| start loss | 0 | |||||
| frameshift | 0 | |||||
| splice donor/acceptor (+/-2bp) | 0 | |||||
| Total | 0 | 1 | 17 | 4 | 0 | 22 |
Highest pathogenic variant AF is 0.00001116908
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_006604.1 | 5 | MANE Select | |
| Ensembl | ENSP00000284154.5 | 5 | MANE Select | |
| RefSeq | NP_001317077.1 | 4 | Standard | |
| Ensembl | ENSP00000378997.1 | 4 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- EGF-Core
- IGF-Ncore
- IGF-Core
- Signal Transduction
- TCR
Biological Process
- Ras protein signal transduction
- cell-cell signaling
- positive regulation of signal transduction
Molecular Function
- SH3/SH2 adaptor activity
- protein binding
Cellular Component
- cytoplasm
- cytosol
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000284154
- Coding exons
- 5
- Length
- 26965
- Individuals with no LoFs
- 124531
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 2
- Defined
- 124533
- p
- 0.00000803
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 1.14 | 49 | 77.1 | 0.635 | 0.00000524 | 1392 |
| Missense (PolyPhen) | 9 | 25.686 | 0.35038 | 533 | ||
| Synonymous | 0.504 | 30 | 33.7 | 0.890 | 0.00000237 | 410 |
| Loss of Function | 1.28 | 2 | 5.13 | 0.390 | 2.17e-7 | 120 |
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 | 0.000055 | 0.000054 | rare |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0 | 0.0 | absent |
| South Asian | 0 | 0.0 | absent |
| Other | 0.00016 | 0.00016 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Couples signals from receptor and cytoplasmic tyrosine kinases to the Ras signaling pathway.;
Recessive Scores
- pRec
- 0.147
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 |