RASGRP4
protein-codingRAS guanyl releasing protein 4, the group of EF-hand domain containing
Gene summary
The protein encoded by this gene is a member of the Ras guanyl nucleotide-releasing protein (RasGRP) family of Ras guanine nucleotide exchange factors. It contains a Ras exchange motif, a diacylglycerol-binding domain, and two calcium-binding EF hands. This protein was shown to activate H-Ras in a cation-dependent manner in vitro. Expression of this protein in myeloid cell lines was found to be correlated with elevated level of activated RAS protein, and the RAS activation can be greatly enhanced by phorbol ester treatment, which suggested a role of this protein in diacylglycerol regulated cell signaling pathways. Studies of a mast cell leukemia cell line expressing substantial amounts of abnormal transcripts of this gene indicated that this gene may play an important role in the final stages of mast cell development. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2009]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~17.3 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 RASGRP4 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_170604.3. 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 | 2 | 1 | 3 | |||
| missense | 92 | 5 | 1 | 98 | ||
| nonsense | 0 | |||||
| start loss | 0 | |||||
| frameshift | 0 | |||||
| splice donor/acceptor (+/-2bp) | 2 | 2 | ||||
| Total | 0 | 0 | 96 | 5 | 2 | 103 |
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_733749.1 | 17 | MANE Select | |
| Ensembl | ENSP00000479844.1 | 17 | MANE Select | |
| RefSeq | NP_001139674.1 | 17 | Standard | |
| RefSeq | NP_001139675.1 | 16 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| rasgrp4 | Danio rerio | Structure: thoracic duct Quality: hypoplastic abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Ras signaling pathway - Homo sapiens (human)
- MAPK signaling pathway - Homo sapiens (human)
- Pathways in cancer - Homo sapiens (human)
- MAPK Signaling Pathway
- Ras Signaling
Biological Process
- MAPK cascade
- transmembrane receptor protein tyrosine kinase signaling pathway
- activation of phospholipase C activity
- small GTPase mediated signal transduction
- regulation of G protein-coupled receptor signaling pathway
Molecular Function
- Ras guanyl-nucleotide exchange factor activity
- calcium ion binding
- diacylglycerol binding
- GTP-dependent protein binding
Cellular Component
- cytosol
- plasma membrane
- membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000587738
- Coding exons
- 17
- Length
- 17251
- Individuals with no LoFs
- 124636
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 28
- Defined
- 124664
- p
- 0.000112
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 2.05 | 291 | 408 | 0.714 | 0.0000250 | 4299 |
| Missense (PolyPhen) | 92 | 160.45 | 0.57341 | 1793 | ||
| Synonymous | 1.29 | 142 | 163 | 0.871 | 0.00000974 | 1356 |
| Loss of Function | 4.11 | 10 | 37.0 | 0.270 | 0.00000214 | 378 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.000065 | 0.000065 | rare |
| Latino/Admixed American | 0.00021 | 0.00020 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.00017 | 0.00017 | rare |
| Finnish | 0.000049 | 0.000046 | rare |
| European (Non-Finnish) | 0.00014 | 0.00013 | rare |
| South Asian | 0.000036 | 0.000033 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Functions as a cation- and diacylglycerol (DAG)- regulated nucleotide exchange factor activating Ras through the exchange of bound GDP for GTP. May function in mast cells differentiation. {ECO:0000269|PubMed:11880369, ECO:0000269|PubMed:11956218, ECO:0000269|PubMed:12493770, ECO:0000269|PubMed:18024961}.;
Recessive Scores
- pRec
- 0.103
Intolerance Scores
- LoFtool
- 0.668
- RVIS EVS
- -0.04
- RVIS percentile EVS
- 50.5
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- N
- Indispensability score
- 0.481
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |