Variant 19-38415075-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The ENST00000615439.5(RASGRP4):c.1003C>G(p.Arg335Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00383 in 1,601,554 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R335C) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0044 ( 4 hom., cov: 33)

Exomes 𝑓: 0.0038 ( 20 hom. )

Consequence

RASGRP4
ENST00000615439.5 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.459

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0049703717).

BP6

Variant 19-38415075-G-C is Benign according to our data. Variant chr19-38415075-G-C is described in ClinVar as [Benign]. Clinvar id is 774354.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RASGRP4	NM_170604.3 linkuse as main transcript	c.1003C>G	p.Arg335Gly	missense_variant	9/17	ENST00000615439.5	NP_733749.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RASGRP4	ENST00000615439.5 linkuse as main transcript	c.1003C>G	p.Arg335Gly	missense_variant	9/17	1	NM_170604.3	ENSP00000479844	P1	Q8TDF6-1

Frequencies

GnomAD3 genomes

AF:

0.00436

AC:

664

AN:

152238

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000724

Gnomad AMI

AF:

0.00987

Gnomad AMR

AF:

0.00137

Gnomad ASJ

AF:

0.00202

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0175

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00595

Gnomad OTH

AF:

0.00287

GnomAD3 exomes

AF:

0.00424

AC:

945

AN:

222698

Hom.:

AF XY:

0.00391

AC XY:

477

AN XY:

122120

show subpopulations

Gnomad AFR exome

AF:

0.000662

Gnomad AMR exome

AF:

0.00126

Gnomad ASJ exome

AF:

0.00234

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0189

Gnomad NFE exome

AF:

0.00482

Gnomad OTH exome

AF:

0.00469

GnomAD4 exome

AF:

0.00377

AC:

5463

AN:

1449198

Hom.:

Cov.:

AF XY:

0.00378

AC XY:

2721

AN XY:

719652

show subpopulations

Gnomad4 AFR exome

AF:

0.000421

Gnomad4 AMR exome

AF:

0.00119

Gnomad4 ASJ exome

AF:

0.00279

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000118

Gnomad4 FIN exome

AF:

0.0183

Gnomad4 NFE exome

AF:

0.00376

Gnomad4 OTH exome

AF:

0.00348

GnomAD4 genome

AF:

0.00436

AC:

664

AN:

152356

Hom.:

Cov.:

AF XY:

0.00458

AC XY:

341

AN XY:

74502

show subpopulations

Gnomad4 AFR

AF:

0.000722

Gnomad4 AMR

AF:

0.00137

Gnomad4 ASJ

AF:

0.00202

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0175

Gnomad4 NFE

AF:

0.00595

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.00473

Hom.:

Bravo

AF:

0.00283

TwinsUK

AF:

0.00270

AC:

ALSPAC

AF:

0.00285

AC:

ExAC

AF:

0.00384

AC:

463

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 08, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.082

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.62

CADD

Benign

5.5

DANN

Uncertain

0.98

DEOGEN2

Benign

0.025

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

Eigen

Benign

-0.87

Eigen_PC

Benign

-0.94

FATHMM_MKL

Benign

0.15

LIST_S2

Benign

0.36

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

MetaRNN

Benign

0.0050

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

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.34

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

MutationTaster

Benign

1.0

N;N;N;N;N;N;N

PrimateAI

Benign

0.27

PROVEAN

Benign

-1.5

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

REVEL

Benign

0.025

Sift

Benign

0.15

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

Sift4G

Benign

0.15

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

Polyphen

0.034

B;.;.;.;.;B;B

Vest4

0.18

MVP

0.072

MPC

0.46

ClinPred

0.013

GERP RS

-2.9

Varity_R

0.19

gMVP

0.24

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