chr19-38414924-C-T

Position:

chr19-38414924-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_170604.3(RASGRP4):c.1154G>A(p.Arg385Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,612,594 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: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

RASGRP4
NM_170604.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.45

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.2965747).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RASGRP4	NM_170604.3 linkuse as main transcript	c.1154G>A	p.Arg385Gln	missense_variant	9/17	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.1154G>A	p.Arg385Gln	missense_variant	9/17	1	NM_170604.3	ENSP00000479844.1	Q8TDF6-1
RASGRP4	ENST00000587738.2 linkuse as main transcript	c.1154G>A	p.Arg385Gln	missense_variant	9/17	5		ENSP00000465772.1	Q8TDF6-1
RASGRP4	ENST00000586305.5 linkuse as main transcript	c.1112G>A	p.Arg371Gln	missense_variant	9/17	1		ENSP00000467604.1	Q8TDF6-2
RASGRP4	ENST00000454404.6 linkuse as main transcript	c.1052G>A	p.Arg351Gln	missense_variant	9/17	1		ENSP00000416463.2	Q8TDF6-8
RASGRP4	ENST00000617966.4 linkuse as main transcript	c.863G>A	p.Arg288Gln	missense_variant	7/15	5		ENSP00000479888.1	Q8TDF6-7
RASGRP4	ENST00000587753.5 linkuse as main transcript	c.955-8G>A		splice_region_variant, intron_variant		1		ENSP00000468483.1	Q8TDF6-9
RASGRP4	ENST00000614135.4 linkuse as main transcript	c.955-1450G>A		intron_variant		5		ENSP00000479078.1	Q8TDF6-5
RASGRP4	ENST00000622174.4 linkuse as main transcript	c.664-1450G>A		intron_variant		5		ENSP00000484345.1	Q8TDF6-6
RASGRP4	ENST00000589358.5 linkuse as main transcript	n.1154G>A		non_coding_transcript_exon_variant	9/18	5		ENSP00000465742.1	Q8TDF6-1
RASGRP4	ENST00000589474.5 linkuse as main transcript	n.1112G>A		non_coding_transcript_exon_variant	9/18	5		ENSP00000466928.1	Q8TDF6-2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000408

AC:

AN:

245030

Hom.:

AF XY:

0.00

AC XY:

AN XY:

133608

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.00000903

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000411

AC:

AN:

1460398

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

726438

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

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:

0.00000450

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152196

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74366

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000508

Hom.:

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

Dec 28, 2022

The c.1154G>A (p.R385Q) alteration is located in exon 9 (coding exon 9) of the RASGRP4 gene. This alteration results from a G to A substitution at nucleotide position 1154, causing the arginine (R) at amino acid position 385 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

0.12

BayesDel_addAF

Benign

-0.10

BayesDel_noAF

Benign

-0.38

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.016

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

Eigen

Uncertain

0.39

Eigen_PC

Uncertain

0.43

FATHMM_MKL

Benign

0.58

LIST_S2

Benign

0.78

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

M_CAP

Benign

0.0077

MetaRNN

Benign

0.30

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

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.0

.;.;.;.;.;L;L

PrimateAI

Benign

0.39

PROVEAN

Benign

-0.68

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

REVEL

Benign

0.084

Sift

Benign

0.17

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

Sift4G

Benign

0.55

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

Polyphen

0.99

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

Vest4

0.17

MutPred

0.41

.;.;.;Loss of stability (P = 0.2348);.;Loss of stability (P = 0.2348);Loss of stability (P = 0.2348);

MVP

0.46

MPC

1.1

ClinPred

0.88

GERP RS

5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.43

gMVP

0.44

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.090

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