19-38412764-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_170604.3(RASGRP4):​c.1588G>A​(p.Ala530Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000687 in 1,456,486 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000069 ( 0 hom. )

Consequence

RASGRP4
NM_170604.3 missense

Scores

7
12

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.901
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 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.13243341).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
RASGRP4NM_170604.3 linkc.1588G>A p.Ala530Thr missense_variant Exon 13 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.1588G>A p.Ala530Thr missense_variant Exon 13 of 17 1 NM_170604.3 ENSP00000479844.1 Q8TDF6-1
RASGRP4ENST00000587738.2 linkc.1588G>A p.Ala530Thr missense_variant Exon 13 of 17 5 ENSP00000465772.1 Q8TDF6-1
RASGRP4ENST00000586305.5 linkc.1546G>A p.Ala516Thr missense_variant Exon 13 of 17 1 ENSP00000467604.1 Q8TDF6-2
RASGRP4ENST00000454404.6 linkc.1486G>A p.Ala496Thr missense_variant Exon 13 of 17 1 ENSP00000416463.2 Q8TDF6-8
RASGRP4ENST00000587753.5 linkc.1381G>A p.Ala461Thr missense_variant Exon 13 of 17 1 ENSP00000468483.1 Q8TDF6-9
RASGRP4ENST00000614135.4 linkc.1312G>A p.Ala438Thr missense_variant Exon 12 of 16 5 ENSP00000479078.1 Q8TDF6-5
RASGRP4ENST00000617966.4 linkc.1297G>A p.Ala433Thr missense_variant Exon 11 of 15 5 ENSP00000479888.1 Q8TDF6-7
RASGRP4ENST00000622174.4 linkc.1021G>A p.Ala341Thr missense_variant Exon 10 of 14 5 ENSP00000484345.1 Q8TDF6-6
RASGRP4ENST00000589358.5 linkn.1588G>A non_coding_transcript_exon_variant Exon 13 of 18 5 ENSP00000465742.1 Q8TDF6-1
RASGRP4ENST00000589474.5 linkn.1546G>A non_coding_transcript_exon_variant Exon 13 of 18 5 ENSP00000466928.1 Q8TDF6-2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000687
AC:
10
AN:
1456486
Hom.:
0
Cov.:
32
AF XY:
0.00000967
AC XY:
7
AN XY:
724174
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000253
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000811
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
Alfa
AF:
0.0000329
Hom.:
0
Bravo
AF:
0.00000378
ExAC
AF:
0.00000827
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Aug 19, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.1588G>A (p.A530T) alteration is located in exon 13 (coding exon 13) of the RASGRP4 gene. This alteration results from a G to A substitution at nucleotide position 1588, causing the alanine (A) at amino acid position 530 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.077
BayesDel_addAF
Uncertain
0.032
T
BayesDel_noAF
Benign
-0.19
CADD
Benign
20
DANN
Uncertain
1.0
DEOGEN2
Benign
0.027
.;.;.;.;.;.;T;.;.;T;.;T
Eigen
Benign
0.0071
Eigen_PC
Benign
0.040
FATHMM_MKL
Benign
0.30
N
LIST_S2
Uncertain
0.95
.;.;.;D;D;.;D;D;D;D;D;.
M_CAP
Benign
0.040
D
MetaRNN
Benign
0.13
T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Uncertain
0.22
D
MutationAssessor
Benign
1.4
.;.;.;.;.;.;.;.;.;L;.;L
PrimateAI
Uncertain
0.51
T
PROVEAN
Benign
-1.3
.;.;.;.;.;.;.;N;N;.;N;.
REVEL
Uncertain
0.31
Sift
Uncertain
0.021
.;.;.;.;.;.;.;D;D;.;D;.
Sift4G
Benign
0.18
T;T;T;T;T;T;T;T;T;T;T;T
Polyphen
0.88
P;.;.;.;.;.;.;.;.;D;.;D
Vest4
0.13
MutPred
0.39
.;.;.;.;.;.;Gain of helix (P = 0.062);.;.;Gain of helix (P = 0.062);.;Gain of helix (P = 0.062);
MVP
0.84
MPC
0.29
ClinPred
0.65
D
GERP RS
4.5
Varity_R
0.073
gMVP
0.43

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

LitVar

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

Other links and lift over

dbSNP: rs766560217; hg19: chr19-38903404; COSMIC: COSV53040334; COSMIC: COSV53040334; API