19-38412988-C-T

Position:

chr19-38412988-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.1478G>A(p.Arg493Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,461,704 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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)

Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

RASGRP4
NM_170604.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.25

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]

RASGRP4 links:

RASGRP4 (HGNC:):

RASGRP4 links:

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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=0.18177128).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RASGRP4	NM_170604.3 linkuse as main transcript	c.1478G>A	p.Arg493Gln	missense_variant	12/17	ENST00000615439.5	NP_733749.1	Q8TDF6-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
RASGRP4	ENST00000615439.5 linkuse as main transcript	c.1478G>A	p.Arg493Gln	missense_variant	12/17	1	NM_170604.3	ENSP00000479844.1	Q8TDF6-1
RASGRP4	ENST00000587738.2 linkuse as main transcript	c.1478G>A	p.Arg493Gln	missense_variant	12/17	5		ENSP00000465772.1	Q8TDF6-1
RASGRP4	ENST00000586305.5 linkuse as main transcript	c.1436G>A	p.Arg479Gln	missense_variant	12/17	1		ENSP00000467604.1	Q8TDF6-2
RASGRP4	ENST00000454404.6 linkuse as main transcript	c.1376G>A	p.Arg459Gln	missense_variant	12/17	1		ENSP00000416463.2	Q8TDF6-8
RASGRP4	ENST00000587753.5 linkuse as main transcript	c.1271G>A	p.Arg424Gln	missense_variant	12/17	1		ENSP00000468483.1	Q8TDF6-9
RASGRP4	ENST00000614135.4 linkuse as main transcript	c.1202G>A	p.Arg401Gln	missense_variant	11/16	5		ENSP00000479078.1	Q8TDF6-5
RASGRP4	ENST00000617966.4 linkuse as main transcript	c.1187G>A	p.Arg396Gln	missense_variant	10/15	5		ENSP00000479888.1	Q8TDF6-7
RASGRP4	ENST00000622174.4 linkuse as main transcript	c.911G>A	p.Arg304Gln	missense_variant	9/14	5		ENSP00000484345.1	Q8TDF6-6
RASGRP4	ENST00000589358.5 linkuse as main transcript	n.1478G>A		non_coding_transcript_exon_variant	12/18	5		ENSP00000465742.1	Q8TDF6-1
RASGRP4	ENST00000589474.5 linkuse as main transcript	n.1436G>A		non_coding_transcript_exon_variant	12/18	5		ENSP00000466928.1	Q8TDF6-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000802

AC:

AN:

249278

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135246

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000885

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000616

AC:

AN:

1461704

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

727138

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000720

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000468

Hom.:

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 27, 2024

The c.1478G>A (p.R493Q) alteration is located in exon 12 (coding exon 12) of the RASGRP4 gene. This alteration results from a G to A substitution at nucleotide position 1478, causing the arginine (R) at amino acid position 493 to be replaced by a glutamine (Q). 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

0.078

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.40

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.010

.;.;.;.;.;.;T;.;.;T;.;T

Eigen

Benign

-0.37

Eigen_PC

Benign

-0.26

FATHMM_MKL

Benign

0.43

LIST_S2

Uncertain

0.94

.;.;.;D;D;.;D;D;D;D;D;.

M_CAP

Benign

0.030

MetaRNN

Benign

0.18

T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.71

MutationAssessor

Benign

-0.20

.;.;.;.;.;.;.;.;.;N;.;N

PrimateAI

Benign

0.41

PROVEAN

Benign

-1.3

.;.;.;.;.;.;.;N;N;.;N;.

REVEL

Benign

0.047

Sift

Benign

0.37

.;.;.;.;.;.;.;T;T;.;T;.

Sift4G

Benign

0.51

T;T;T;T;T;T;T;T;T;T;T;T

Polyphen

0.77

P;.;.;.;.;.;.;.;.;P;.;P

Vest4

0.37

MutPred

0.34

.;.;.;.;.;.;Gain of helix (P = 0.0425);.;.;Gain of helix (P = 0.0425);.;Gain of helix (P = 0.0425);

MVP

0.66

MPC

0.57

ClinPred

0.48

GERP RS

3.7

Varity_R

0.086

gMVP

0.23

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over