Variant chr19-38422124-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_170604.3(RASGRP4):c.53T>C(p.Ile18Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.386 in 1,610,698 control chromosomes in the GnomAD database, including 125,314 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.44 ( 15742 hom., cov: 33)

Exomes 𝑓: 0.38 ( 109572 hom. )

Consequence

RASGRP4
NM_170604.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.84

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 -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=1.9170338E-5).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.587 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RASGRP4	NM_170604.3 linkuse as main transcript	c.53T>C	p.Ile18Thr	missense_variant	2/17	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.53T>C	p.Ile18Thr	missense_variant	2/17	1	NM_170604.3	ENSP00000479844	P1	Q8TDF6-1

Frequencies

GnomAD3 genomes

AF:

0.440

AC:

66712

AN:

151776

Hom.:

15694

Cov.:

show subpopulations

Gnomad AFR

AF:

0.592

Gnomad AMI

AF:

0.166

Gnomad AMR

AF:

0.415

Gnomad ASJ

AF:

0.381

Gnomad EAS

AF:

0.554

Gnomad SAS

AF:

0.582

Gnomad FIN

AF:

0.405

Gnomad MID

AF:

0.358

Gnomad NFE

AF:

0.347

Gnomad OTH

AF:

0.408

GnomAD3 exomes

AF:

0.429

AC:

105128

AN:

245178

Hom.:

23808

AF XY:

0.427

AC XY:

56966

AN XY:

133304

show subpopulations

Gnomad AFR exome

AF:

0.600

Gnomad AMR exome

AF:

0.471

Gnomad ASJ exome

AF:

0.384

Gnomad EAS exome

AF:

0.552

Gnomad SAS exome

AF:

0.574

Gnomad FIN exome

AF:

0.405

Gnomad NFE exome

AF:

0.343

Gnomad OTH exome

AF:

0.386

GnomAD4 exome

AF:

0.380

AC:

554222

AN:

1458804

Hom.:

109572

Cov.:

AF XY:

0.384

AC XY:

278649

AN XY:

725706

show subpopulations

Gnomad4 AFR exome

AF:

0.596

Gnomad4 AMR exome

AF:

0.470

Gnomad4 ASJ exome

AF:

0.395

Gnomad4 EAS exome

AF:

0.520

Gnomad4 SAS exome

AF:

0.564

Gnomad4 FIN exome

AF:

0.401

Gnomad4 NFE exome

AF:

0.349

Gnomad4 OTH exome

AF:

0.394

GnomAD4 genome

AF:

0.440

AC:

66826

AN:

151894

Hom.:

15742

Cov.:

AF XY:

0.447

AC XY:

33218

AN XY:

74240

show subpopulations

Gnomad4 AFR

AF:

0.593

Gnomad4 AMR

AF:

0.415

Gnomad4 ASJ

AF:

0.381

Gnomad4 EAS

AF:

0.554

Gnomad4 SAS

AF:

0.583

Gnomad4 FIN

AF:

0.405

Gnomad4 NFE

AF:

0.347

Gnomad4 OTH

AF:

0.415

Alfa

AF:

0.367

Hom.:

27279

Bravo

AF:

0.446

TwinsUK

AF:

0.357

AC:

1323

ALSPAC

AF:

0.362

AC:

1395

ESP6500AA

AF:

0.579

AC:

2221

ESP6500EA

AF:

0.353

AC:

2908

ExAC

AF:

0.426

AC:

51503

Asia WGS

AF:

0.616

AC:

2139

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.045

BayesDel_addAF

Benign

-0.79

BayesDel_noAF

Benign

-0.77

CADD

Benign

DANN

Benign

0.15

DEOGEN2

Benign

0.0029

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

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.00083

LIST_S2

Benign

0.16

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

MetaRNN

Benign

0.000019

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

MetaSVM

Benign

-0.93

MutationAssessor

Benign

-1.6

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

MutationTaster

Benign

1.0

P;P;P;P;P;P;P

PrimateAI

Benign

0.41

PROVEAN

Benign

0.63

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

REVEL

Benign

0.11

Sift

Benign

1.0

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

Sift4G

Benign

0.53

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

Polyphen

0.0

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

Vest4

0.0070

MPC

0.35

ClinPred

0.0034

GERP RS

4.1

Varity_R

0.031

gMVP

0.12

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over