rs375300341

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_170604.3(RASGRP4):c.1579C>T(p.Arg527Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000634 in 1,607,586 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000049 ( 1 hom. )

Consequence

RASGRP4
NM_170604.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.39

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:

Genome browser will be placed here

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=0.14375854).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RASGRP4	NM_170604.3 link	c.1579C>T	p.Arg527Trp	missense_variant	Exon 13 of 17	ENST00000615439.5	NP_733749.1	Q8TDF6-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
RASGRP4	ENST00000615439.5 link	c.1579C>T	p.Arg527Trp	missense_variant	Exon 13 of 17	1	NM_170604.3	ENSP00000479844.1	Q8TDF6-1
RASGRP4	ENST00000587738.2 link	c.1579C>T	p.Arg527Trp	missense_variant	Exon 13 of 17	5		ENSP00000465772.1	Q8TDF6-1
RASGRP4	ENST00000586305.5 link	c.1537C>T	p.Arg513Trp	missense_variant	Exon 13 of 17	1		ENSP00000467604.1	Q8TDF6-2
RASGRP4	ENST00000454404.6 link	c.1477C>T	p.Arg493Trp	missense_variant	Exon 13 of 17	1		ENSP00000416463.2	Q8TDF6-8
RASGRP4	ENST00000587753.5 link	c.1372C>T	p.Arg458Trp	missense_variant	Exon 13 of 17	1		ENSP00000468483.1	Q8TDF6-9
RASGRP4	ENST00000614135.4 link	c.1303C>T	p.Arg435Trp	missense_variant	Exon 12 of 16	5		ENSP00000479078.1	Q8TDF6-5
RASGRP4	ENST00000617966.4 link	c.1288C>T	p.Arg430Trp	missense_variant	Exon 11 of 15	5		ENSP00000479888.1	Q8TDF6-7
RASGRP4	ENST00000622174.4 link	c.1012C>T	p.Arg338Trp	missense_variant	Exon 10 of 14	5		ENSP00000484345.1	Q8TDF6-6
RASGRP4	ENST00000589358.5 link	n.1579C>T		non_coding_transcript_exon_variant	Exon 13 of 18	5		ENSP00000465742.1	Q8TDF6-1
RASGRP4	ENST00000589474.5 link	n.1537C>T		non_coding_transcript_exon_variant	Exon 13 of 18	5		ENSP00000466928.1	Q8TDF6-2

Frequencies

GnomAD3 genomes

AF:

0.000204

AC:

AN:

152174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000507

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000964

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000102

AC:

AN:

234638

Hom.:

AF XY:

0.000110

AC XY:

AN XY:

127424

show subpopulations

Gnomad AFR exome

AF:

0.000562

Gnomad AMR exome

AF:

0.0000926

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000474

Gnomad SAS exome

AF:

0.0000340

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000380

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000488

AC:

AN:

1455294

Hom.:

Cov.:

AF XY:

0.0000553

AC XY:

AN XY:

723478

show subpopulations

Gnomad4 AFR exome

AF:

0.000420

Gnomad4 AMR exome

AF:

0.0000463

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000558

Gnomad4 SAS exome

AF:

0.000129

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000153

Gnomad4 OTH exome

AF:

0.0000499

GnomAD4 genome

AF:

0.000204

AC:

AN:

152292

Hom.:

Cov.:

AF XY:

0.000201

AC XY:

AN XY:

74456

show subpopulations

Gnomad4 AFR

AF:

0.000505

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000966

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000127

Hom.:

Bravo

AF:

0.000113

ESP6500AA

AF:

0.000242

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000116

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jul 27, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1579C>T (p.R527W) alteration is located in exon 13 (coding exon 13) of the RASGRP4 gene. This alteration results from a C to T substitution at nucleotide position 1579, causing the arginine (R) at amino acid position 527 to be replaced by a tryptophan (W). 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

-0.11

BayesDel_noAF

Uncertain

-0.020

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.23

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

Eigen

Uncertain

0.55

Eigen_PC

Uncertain

0.51

FATHMM_MKL

Benign

0.66

LIST_S2

Uncertain

0.97

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

M_CAP

Benign

0.058

MetaRNN

Benign

0.14

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

MetaSVM

Uncertain

0.69

MutationAssessor

Uncertain

2.1

.;.;.;.;.;.;.;.;.;M;.;M

PrimateAI

Benign

0.38

PROVEAN

Uncertain

-4.1

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

REVEL

Uncertain

0.47

Sift

Uncertain

0.014

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

Sift4G

Pathogenic

0.0010

D;D;D;D;D;D;D;D;D;D;D;D

Polyphen

1.0

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

Vest4

0.44

MVP

0.81

MPC

0.79

ClinPred

0.25

GERP RS

4.5

Varity_R

0.62

gMVP

0.77

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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