rs186928850

Variant summary

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

The NM_170604.3(RASGRP4):​c.1490A>T​(p.Asn497Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Consequence

RASGRP4
NM_170604.3 missense

Scores

1
5
13

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.52
Variant links:
Genes affected
RASGRP4 (HGNC:18958): (RAS guanyl releasing protein 4) 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]

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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 rank MANE Protein UniProt
RASGRP4NM_170604.3 linkc.1490A>T p.Asn497Ile missense_variant Exon 12 of 17 ENST00000615439.5 NP_733749.1 Q8TDF6-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
RASGRP4ENST00000615439.5 linkc.1490A>T p.Asn497Ile missense_variant Exon 12 of 17 1 NM_170604.3 ENSP00000479844.1 Q8TDF6-1
RASGRP4ENST00000587738.2 linkc.1490A>T p.Asn497Ile missense_variant Exon 12 of 17 5 ENSP00000465772.1 Q8TDF6-1
RASGRP4ENST00000586305.5 linkc.1448A>T p.Asn483Ile missense_variant Exon 12 of 17 1 ENSP00000467604.1 Q8TDF6-2
RASGRP4ENST00000454404.6 linkc.1388A>T p.Asn463Ile missense_variant Exon 12 of 17 1 ENSP00000416463.2 Q8TDF6-8
RASGRP4ENST00000587753.5 linkc.1283A>T p.Asn428Ile missense_variant Exon 12 of 17 1 ENSP00000468483.1 Q8TDF6-9
RASGRP4ENST00000614135.4 linkc.1214A>T p.Asn405Ile missense_variant Exon 11 of 16 5 ENSP00000479078.1 Q8TDF6-5
RASGRP4ENST00000617966.4 linkc.1199A>T p.Asn400Ile missense_variant Exon 10 of 15 5 ENSP00000479888.1 Q8TDF6-7
RASGRP4ENST00000622174.4 linkc.923A>T p.Asn308Ile missense_variant Exon 9 of 14 5 ENSP00000484345.1 Q8TDF6-6
RASGRP4ENST00000589358.5 linkn.1490A>T non_coding_transcript_exon_variant Exon 12 of 18 5 ENSP00000465742.1 Q8TDF6-1
RASGRP4ENST00000589474.5 linkn.1448A>T non_coding_transcript_exon_variant Exon 12 of 18 5 ENSP00000466928.1 Q8TDF6-2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.22
BayesDel_addAF
Benign
-0.0031
T
BayesDel_noAF
Benign
-0.24
CADD
Benign
23
DANN
Uncertain
0.99
DEOGEN2
Benign
0.23
.;.;.;.;.;.;T;.;.;T;.;T
Eigen
Benign
0.16
Eigen_PC
Benign
0.13
FATHMM_MKL
Uncertain
0.91
D
LIST_S2
Uncertain
0.88
.;.;.;D;D;.;D;D;D;D;D;.
M_CAP
Benign
0.080
D
MetaRNN
Uncertain
0.74
D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Benign
-0.64
T
MutationAssessor
Benign
1.8
.;.;.;.;.;.;.;.;.;L;.;L
PrimateAI
Benign
0.45
T
PROVEAN
Pathogenic
-6.9
.;.;.;.;.;.;.;D;D;.;D;.
REVEL
Benign
0.19
Sift
Benign
0.036
.;.;.;.;.;.;.;D;D;.;D;.
Sift4G
Uncertain
0.0020
D;D;D;D;D;D;D;D;D;D;D;D
Polyphen
0.97
D;.;.;.;.;.;.;.;.;D;.;D
Vest4
0.70
MutPred
0.53
.;.;.;.;.;.;Loss of catalytic residue at N497 (P = 0.002);.;.;Loss of catalytic residue at N497 (P = 0.002);.;Loss of catalytic residue at N497 (P = 0.002);
MVP
0.59
MPC
0.94
ClinPred
0.97
D
GERP RS
1.7
Varity_R
0.36
gMVP
0.65

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs186928850; hg19: chr19-38903616; API