chr15-38490612-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_005739.4(RASGRP1):​c.2336T>A​(p.Leu779His) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Consequence

RASGRP1
NM_005739.4 missense

Scores

5
9
5

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.10
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
RASGRP1NM_005739.4 linkuse as main transcriptc.2336T>A p.Leu779His missense_variant 17/17 ENST00000310803.10 NP_005730.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
RASGRP1ENST00000310803.10 linkuse as main transcriptc.2336T>A p.Leu779His missense_variant 17/171 NM_005739.4 ENSP00000310244 P1O95267-1

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
LINK: link

Submissions by phenotype

not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpOct 19, 2021In 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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals affected with RASGRP1-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces leucine with histidine at codon 779 of the RASGRP1 protein (p.Leu779His). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and histidine. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.36
BayesDel_addAF
Pathogenic
0.39
D
BayesDel_noAF
Pathogenic
0.32
CADD
Pathogenic
26
DANN
Uncertain
0.98
DEOGEN2
Benign
0.18
T;T;T;T;.
Eigen
Uncertain
0.54
Eigen_PC
Uncertain
0.54
FATHMM_MKL
Uncertain
0.91
D
LIST_S2
Benign
0.83
T;T;T;T;T
M_CAP
Pathogenic
0.29
D
MetaRNN
Uncertain
0.58
D;D;D;D;D
MetaSVM
Uncertain
0.30
D
MutationAssessor
Benign
1.0
L;.;.;.;.
MutationTaster
Benign
1.0
D;D;D;D;D;D
PrimateAI
Uncertain
0.57
T
PROVEAN
Benign
-1.1
N;.;N;N;N
REVEL
Uncertain
0.51
Sift
Pathogenic
0.0
D;.;D;D;D
Sift4G
Pathogenic
0.0
D;D;D;D;D
Polyphen
1.0
D;.;.;.;D
Vest4
0.86
MutPred
0.34
Loss of stability (P = 0.0369);Loss of stability (P = 0.0369);.;.;.;
MVP
0.65
MPC
1.4
ClinPred
0.93
D
GERP RS
4.4
Varity_R
0.53
gMVP
0.60

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

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: chr15-38782813; API