chr15-38490688-C-T

Position:

• chr15-38490688-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_005739.4(RASGRP1):​c.2260G>A​(p.Glu754Lys) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RASGRP1 NM_005739.4 missense, splice_region
• Scores: Splicing: ADA: 0.1761
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.67

Genes affected

RASGRP1 (HGNC:9878): (RAS guanyl releasing protein 1) 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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.31761718).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RASGRP1	NM_005739.4	c.2260G>A	p.Glu754Lys	missense_variant, splice_region_variant	17/17	ENST00000310803.10	NP_005730.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RASGRP1	ENST00000310803.10	c.2260G>A	p.Glu754Lys	missense_variant, splice_region_variant	17/17	1	NM_005739.4	ENSP00000310244	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 17, 2023

This variant has not been reported in the literature in individuals affected with RASGRP1-related conditions. This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 754 of the RASGRP1 protein (p.Glu754Lys). This variant is not present in population databases (gnomAD no frequency). ClinVar contains an entry for this variant (Variation ID: 1996833). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.070
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.16	T;T;T;T;.
Eigen	Benign	0.011
Eigen_PC	Benign	0.10
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.88	D;D;D;D;D
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.32	T;T;T;T;T
MetaSVM	Benign	-0.96	T
MutationTaster	Benign	1.0	D;D;D;D;N;N
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-1.0	N;.;N;N;N
REVEL	Uncertain	0.44
Sift	Uncertain	0.0030	D;.;D;D;D
Sift4G	Uncertain	0.039	D;D;D;D;D
Polyphen		0.71	P;.;.;.;P
Vest4		0.45
MutPred		0.28		Gain of ubiquitination at E754 (P = 0.0177);Gain of ubiquitination at E754 (P = 0.0177);.;.;.;
MVP		0.51
MPC		0.49
ClinPred		0.96	D
GERP RS		3.5
Varity_R		0.47
gMVP		0.76

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.18
dbscSNV1_RF	Benign	0.39
SpliceAI score (max)		0.53		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.53		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr15-38782889; COSMIC: COSV60366916; COSMIC: COSV60366916;