RASGRP1

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

Basic information

Region (hg38): 15:38488102-38565575

Links

ENSG00000172575 ∙ NCBI:10125 ∙ OMIM:603962 ∙ HGNC:9878 ∙ Uniprot:O95267 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• autoimmune lymphoproliferative syndrome (Supportive), mode of inheritance: AD
• immunodeficiency 64 (Strong), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Immunodeficiency 64 with lymphoproliferation	AR	Allergy/Immunology/Infectious; Oncologic	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	Allergy/Immunology/Infectious; Oncologic	27776107; 28822832; 29155103; 29282224

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the RASGRP1 gene.

• not provided (275 variants)
• Inborn genetic diseases (16 variants)
• Immunodeficiency 64 (14 variants)
• not specified (12 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the RASGRP1 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			3	72	9	84
missense			125	5	1	131
nonsense	5		2			7
start loss			1			1
frameshift	5					5
inframe indel			2			2
splice donor/acceptor (+/-2bp)	1	3				4
splice region			9	9	1	19
non coding			3	37	7	47
Total	11	3	136	114	17

Highest pathogenic variant AF is 0.00000657

Variants in RASGRP1

This is a list of pathogenic ClinVar variants found in the RASGRP1 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
15-38490554-C-T			Likely benign (Dec 06, 2023)
15-38490566-A-G			Likely benign (Feb 21, 2022)
15-38490567-C-T			Uncertain significance (Jul 12, 2021)
15-38490580-G-A			Uncertain significance (Nov 04, 2021)
15-38490591-T-C			Uncertain significance (Mar 07, 2021)
15-38490599-T-C			Likely benign (Sep 17, 2023)
15-38490608-C-G			Uncertain significance (Nov 30, 2021)
15-38490612-A-T			Uncertain significance (Oct 19, 2021)
15-38490614-G-A			Likely benign (Feb 18, 2023)
15-38490621-A-G			Uncertain significance (Nov 07, 2023)
15-38490653-T-C			Likely benign (Oct 06, 2021)
15-38490667-C-A			Uncertain significance (Jan 31, 2022)
15-38490679-T-A		not specified	Uncertain significance (Mar 23, 2022)
15-38490688-C-T			Uncertain significance (Jul 17, 2023)
15-38490694-G-C			Uncertain significance (Jan 28, 2021)
15-38490700-G-A			Likely benign (Jan 19, 2024)
15-38490701-G-A			Likely benign (Dec 01, 2023)
15-38494393-C-T		not specified	Uncertain significance (Jun 24, 2022)
15-38494397-G-A			Likely benign (Oct 04, 2023)
15-38494403-A-G			Likely benign (Jan 27, 2022)
15-38494412-G-C		RASGRP1-related disorder	Likely benign (Oct 26, 2023)
15-38494419-C-T			Uncertain significance (Feb 24, 2022)
15-38494420-G-A			Uncertain significance (Aug 16, 2022)
15-38494421-G-A			Likely benign (Jun 27, 2022)
15-38494432-T-C			Uncertain significance (Jun 10, 2022)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
RASGRP1	protein_coding	protein_coding	ENST00000310803	17	77473

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.966	0.0345	124641	0	17	124658	0.0000682

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	2.74	259	417	0.622	0.0000213	5211
Missense in 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

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.0000291	0.0000291
Ashkenazi Jewish	0.000199	0.000199
East Asian	0.0000566	0.0000556
Finnish	0.0000939	0.0000928
European (Non-Finnish)	0.0000717	0.0000708
Middle Eastern	0.0000566	0.0000556
South Asian	0.0000983	0.0000980
Other	0.00	0.00

dbNSFP

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.
• Pathway: 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);T-Cell Receptor and Co-stimulatory Signaling;Vitamin D Receptor Pathway;MAPK Signaling Pathway;Ras Signaling;Serotonin HTR1 Group and FOS Pathway;Serotonin Receptor 2 and ELK-SRF-GATA4 signaling;Signaling by GPCR;Regulation of Ras family activation;Signal Transduction;Activation of RAS in B cells;Signaling by the B Cell Receptor (BCR);CD4 T cell receptor signaling-ERK cascade;Integrin alphaIIb beta3 signaling;Fc epsilon receptor (FCERI) signaling;TCR;Innate Immune System;Immune System;Rap1 signalling;Adaptive Immune System;Downstream signaling events of B Cell Receptor (BCR);Platelet Aggregation (Plug Formation);Effects of PIP2 hydrolysis;Platelet activation, signaling and aggregation;Integrin signaling;Hemostasis;RAF/MAP kinase cascade;MAPK1/MAPK3 signaling;MAPK family signaling cascades;FCERI mediated NF-kB activation;G alpha (q) signalling events;GPCR downstream signalling;TCR signaling in naïve CD8+ T cells;TCR signaling in naïve CD4+ T cells;CD4 T cell receptor signaling-JNK cascade;CD4 T cell receptor signaling-NFkB cascade;CD4 T cell receptor signaling (Consensus)

Recessive Scores

• pRec: 0.170

Intolerance Scores

• loftool: 0.775
• rvis_EVS: -0.82
• rvis_percentile_EVS: 11.77

Haploinsufficiency Scores

• pHI: 0.363
• hipred: Y
• hipred_score: 0.793
• ghis: 0.576

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.789

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Rasgrp1
• Phenotype: liver/biliary system phenotype; hematopoietic system phenotype; renal/urinary system phenotype; immune system phenotype; endocrine/exocrine gland phenotype

Gene ontology

• Biological process: MAPK cascade;cytokine production;positive regulation of protein phosphorylation;inflammatory response to antigenic stimulus;signal transduction;Ras protein signal transduction;regulation of phosphatidylinositol 3-kinase signaling;cell differentiation;secretory granule localization;positive regulation of granulocyte macrophage colony-stimulating factor production;positive regulation of tumor necrosis factor production;positive regulation of natural killer cell differentiation;positive regulation of T cell differentiation in thymus;mast cell degranulation;positive regulation of MAP kinase activity;positive regulation of GTPase activity;positive regulation of natural killer cell mediated cytotoxicity;positive regulation of JNK cascade;positive regulation of Ras protein signal transduction;vesicle transport along microtubule;protein complex oligomerization;regulation of ERK1 and ERK2 cascade;positive regulation of ERK1 and ERK2 cascade;activation of GTPase activity;regulation of phospholipase C activity;regulation of p38MAPK cascade;positive regulation of interferon-gamma secretion
• Cellular component: Golgi membrane;endoplasmic reticulum membrane;Golgi apparatus;cytosol;plasma membrane;membrane;mast cell granule
• Molecular function: phosphatidylserine binding;guanyl-nucleotide exchange factor activity;Ras guanyl-nucleotide exchange factor activity;GTPase activator activity;calcium ion binding;zinc ion binding;lipid binding;diacylglycerol binding;phosphatidylcholine binding;protein homodimerization activity