RASGRP1

protein-coding

RAS guanyl releasing protein 1, the group of EF-hand domain containing

Gene summary

This gene is a member of a family of genes characterized by the presence of a Ras superfamily guanine nucleotide exchange factor (GEF) domain. It functions as a diacylglycerol (DAG)-regulated nucleotide exchange factor specifically activating Ras through the exchange of bound GDP for GTP. It activates the Erk/MAP kinase cascade and regulates T-cells and B-cells development, homeostasis and differentiation. Alternatively spliced transcript variants encoding different isoforms have been identified. Altered expression of the different isoforms of this protein may be a cause of susceptibility to systemic lupus erythematosus (SLE). [provided by RefSeq, Jul 2008]

MANE transcript

NM_005739.4

Inheritance

ClinVar variants

P:33U:222B:150

Top phenotype

Immunodeficiency 64 with lymphoproliferation

gnomAD constraint

pLI —, LoF o/e 0.17

Max pathogenic AF

—

Genomic locus

chr15:38,488,103-38,565,575

External References & Databases

Ensembl (ENSG00000172575)

Transcript & Mutation Effects

hg38 • Region Span ~77.5 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

immunodeficiency 64STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0032803

Submitter: PanelApp Australia

immunodeficiency 64STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0032803

Submitter: Labcorp Genetics (formerly Invitae)

immunodeficiency 64DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0032803

Submitter: ClinGen

The first patient case reports indicating a relationship of the RASGRP1 gene with immunodeficiency 64 was done by Selzer et al in 2016 (PMID: 8379998). Immunodeficiency 64 is characterized by recurrent bacterial, viral and fungal infections in childhood. Laboratory investigation of patients with immunodeficiency 64 shows decreased numbers of T cells, with less striking decreases in B and NK cells. There has been a documented relationship with immunodeficiency 64 with EBV-associated lymphoma and autoimmunity (Selzer et al, PMID: 8379998 ; Mao et al, PMID 29155103 ; Winter et al, PMID 29282224). Numerous RASGRP1 variants have been reported in ClinVar. Evidence supporting the gene-disease relationship with RASGRP1 includes case-level data, as well as experimental evidence with functional data, data on functional alterations, non-human model organisms and rescue in patient cells. This gene-disease relationship has been studied in patients for almost 10 years with studies of RASGRP1’s molecular function done in the decades prior (mouse model knockouts first made in 2000). Since that time, there has been a wealth of experimental and clinical data to support the maximum score for genetic evidence (12 points) and experimental evidence (6 points). Note, this curation effort may not be exhaustive of all literature related to this gene-disease relationship, as evidence compilation was stopped once maximum scoring was reached. The mechanism for the gene-disease relationship is a protein loss of function, as RASGRP1 is RAS pathway activator, functioning as a DAG-regulated nucleotide exchange factor that preferentially regulates the MAPK pathway. It has been heavily studied in T cell development, survival and proliferation, as well as in activation of the B cell receptor and in NK cell activation (reviewed in Hsu et al, 2023 PMID 36675167). In summary, RASGRP1 is DEFINITIVELY associated with immunodeficiency 64. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen General Gene Curation Expert Panel on June 7, 2024.

Clinical Genomic Database (CGD)

Immunodeficiency 64 with lymphoproliferationAR

Manifestation: Allergy/Immunology/Infectious; Oncologic

Intervention: Allergy/Immunology/Infectious; Oncologic

Rationale: The condition can involve early-onset recurrent bacterial, viral, and fungal infections, and antiinfectious prophylaxis and early and aggressive treatment of infections may be beneficial; Individuals have been increased susceptibility to EBV infection and risk of EBV-associated lymphoma, and awareness may allow prompt diagnosis and management

Refs: 27776107; 28822832; 29155103; 29282224

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to RASGRP1 variants in ClinVar

4 Conditions Cataloged

not providedTotal: 445

not specifiedTotal: 87

Immunodeficiency 64Total: 26

RASGRP1-related disorderTotal: 15

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_005739.4. 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			11 clinvar	140 clinvar	4 clinvar	155
missense	1 clinvar		204 clinvar	5 clinvar	1 clinvar	211
nonsense	11 clinvar	2 clinvar	4 clinvar			17
start loss			1 clinvar			1
frameshift	9 clinvar	1 clinvar				10
splice donor/acceptor (+/-2bp)	2 clinvar	7 clinvar	2 clinvar			11
Total	23	10	222	145	5	405

Highest pathogenic variant AF is 0.000017135137

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 41 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_005739.4	RefSeq	NP_005730.2	17	MANE Select
ENST00000310803.10	Ensembl	ENSP00000310244.5	17	MANE Select
NM_001128602.2	RefSeq	NP_001122074.1	16	Standard
NM_001306086.2	RefSeq	NP_001293015.1	15	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Platelet activation - Homo sapiens (human)
T cell receptor signaling pathway - Homo sapiens (human)
Ras signaling pathway - Homo sapiens (human)
MAPK signaling pathway - Homo sapiens (human)
Pathways in cancer - Homo sapiens (human)

Biological Process

MAPK cascade
cytokine production
positive regulation of protein phosphorylation
inflammatory response to antigenic stimulus
signal transduction

Molecular Function

phosphatidylserine binding
guanyl-nucleotide exchange factor activity
Ras guanyl-nucleotide exchange factor activity
GTPase activator activity
calcium ion binding

Cellular Component

Golgi membrane
endoplasmic reticulum membrane
Golgi apparatus
cytosol
plasma membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000310803
Coding exons: 17
Length: 77473
Individuals with no LoFs: 124641
Homozygous LoFs: 0
Heterozygous LoFs: 17
Defined: 124658
p: 0.0000682

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.74	259	417	0.622	0.0000213	5211
Missense (PolyPhen)		59	148.05	0.39851		1892
Synonymous	1.09	140	157	0.889	0.00000811	1517
Loss of Function	4.95	7	41.3	0.169	0.00000235	476

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000029	0.000029	rare
Ashkenazi Jewish	0.00020	0.00020	rare
East Asian	0.000057	0.000056	rare
Finnish	0.000094	0.000093	rare
European (Non-Finnish)	0.000072	0.000071	rare
South Asian	0.000098	0.000098	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Functions as a calcium- and diacylglycerol (DAG)- regulated nucleotide exchange factor specifically activating Ras through the exchange of bound GDP for GTP (PubMed:15899849, PubMed:23908768). Activates the Erk/MAP kinase cascade (PubMed:15899849). Regulates T-cell/B-cell development, homeostasis and differentiation by coupling T-lymphocyte/B- lymphocyte antigen receptors to Ras (PubMed:10807788, PubMed:12839994). Regulates NK cell cytotoxicity and ITAM- dependent cytokine production by activation of Ras-mediated ERK and JNK pathways (PubMed:19933860). Functions in mast cell degranulation and cytokine secretion, regulating FcERI-evoked allergic responses (By similarity). May also function in differentiation of other cell types (PubMed:12845332). {ECO:0000250|UniProtKB:Q9Z1S3, ECO:0000269|PubMed:10807788, ECO:0000269|PubMed:12782630, ECO:0000269|PubMed:12839994, ECO:0000269|PubMed:12845332, ECO:0000269|PubMed:15060167, ECO:0000269|PubMed:15184873, ECO:0000269|PubMed:15899849, ECO:0000269|PubMed:19933860, ECO:0000269|PubMed:23908768}.;
Disease: DISEASE: Systemic lupus erythematosus (SLE) [MIM:152700]: A chronic, relapsing, inflammatory, and often febrile multisystemic disorder of connective tissue, characterized principally by involvement of the skin, joints, kidneys and serosal membranes. It is of unknown etiology, but is thought to represent a failure of the regulatory mechanisms of the autoimmune system. The disease is marked by a wide range of system dysfunctions, an elevated erythrocyte sedimentation rate, and the formation of LE cells in the blood or bone marrow. {ECO:0000269|PubMed:17878389}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. Aberrantly spliced isoforms and/or diminished levels of RASGRP1 are found in a cohort of SLE patients raising the possibility that dysregulation of this signaling protein contributes to the development of autoimmunity in a subset of SLE patients.;

Recessive Scores

pRec: 0.170

Intolerance Scores

LoFtool: 0.775
RVIS EVS: -0.82
RVIS percentile EVS: 11.77

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.789

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium