chr19-38413281-T-C

Position:

chr19-38413281-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_170604.3(RASGRP4):c.1328A>G(p.Asn443Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000186 in 1,613,118 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/23 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: 𝑓 0.000053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000015 ( 0 hom. )

Consequence

RASGRP4
NM_170604.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.51

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 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RASGRP4	NM_170604.3 linkuse as main transcript	c.1328A>G	p.Asn443Ser	missense_variant	11/17	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.1328A>G	p.Asn443Ser	missense_variant	11/17	1	NM_170604.3	ENSP00000479844.1	Q8TDF6-1
RASGRP4	ENST00000587738.2 linkuse as main transcript	c.1328A>G	p.Asn443Ser	missense_variant	11/17	5		ENSP00000465772.1	Q8TDF6-1
RASGRP4	ENST00000586305.5 linkuse as main transcript	c.1286A>G	p.Asn429Ser	missense_variant	11/17	1		ENSP00000467604.1	Q8TDF6-2
RASGRP4	ENST00000454404.6 linkuse as main transcript	c.1226A>G	p.Asn409Ser	missense_variant	11/17	1		ENSP00000416463.2	Q8TDF6-8
RASGRP4	ENST00000587753.5 linkuse as main transcript	c.1121A>G	p.Asn374Ser	missense_variant	11/17	1		ENSP00000468483.1	Q8TDF6-9
RASGRP4	ENST00000614135.4 linkuse as main transcript	c.1052A>G	p.Asn351Ser	missense_variant	10/16	5		ENSP00000479078.1	Q8TDF6-5
RASGRP4	ENST00000617966.4 linkuse as main transcript	c.1037A>G	p.Asn346Ser	missense_variant	9/15	5		ENSP00000479888.1	Q8TDF6-7
RASGRP4	ENST00000622174.4 linkuse as main transcript	c.761A>G	p.Asn254Ser	missense_variant	8/14	5		ENSP00000484345.1	Q8TDF6-6
RASGRP4	ENST00000589358.5 linkuse as main transcript	n.1328A>G		non_coding_transcript_exon_variant	11/18	5		ENSP00000465742.1	Q8TDF6-1
RASGRP4	ENST00000589474.5 linkuse as main transcript	n.1286A>G		non_coding_transcript_exon_variant	11/18	5		ENSP00000466928.1	Q8TDF6-2

Frequencies

GnomAD3 genomes

AF:

0.0000528

AC:

AN:

151614

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000162

AC:

AN:

247486

Hom.:

AF XY:

0.00

AC XY:

AN XY:

134716

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:

0.0000358

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000151

AC:

AN:

1461504

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

727040

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000198

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000528

AC:

AN:

151614

Hom.:

Cov.:

AF XY:

0.0000405

AC XY:

AN XY:

74034

show subpopulations

Gnomad4 AFR

AF:

0.0000242

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000103

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000988

Hom.:

Bravo

AF:

0.0000302

ExAC

AF:

0.00000828

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

Aug 19, 2024

The c.1328A>G (p.N443S) alteration is located in exon 11 (coding exon 11) of the RASGRP4 gene. This alteration results from a A to G substitution at nucleotide position 1328, causing the asparagine (N) at amino acid position 443 to be replaced by a serine (S). 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

0.056

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.68

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.021

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

Eigen

Benign

-0.33

Eigen_PC

Benign

-0.14

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.66

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

M_CAP

Benign

0.011

MetaRNN

Benign

0.10

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

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.26

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

PrimateAI

Benign

0.35

PROVEAN

Benign

-0.89

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

REVEL

Benign

0.077

Sift

Benign

0.18

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

Sift4G

Benign

0.21

T;T;D;T;T;T;T;T;T;T;D;T

Polyphen

0.014

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

Vest4

0.12

MVP

0.29

MPC

0.23

ClinPred

0.22

GERP RS

4.9

Varity_R

0.081

gMVP

0.20

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.27

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.27

Position offset: -1

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