19-38411347-C-T

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.1715G>A(p.Arg572Gln) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000874 in 1,601,168 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000083 ( 0 hom. )

Consequence

RASGRP4
NM_170604.3 missense, splice_region

Scores

Splicing: ADA: 0.0002085

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.161

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=0.21924457).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RASGRP4	NM_170604.3 link	c.1715G>A	p.Arg572Gln	missense_variant, splice_region_variant	Exon 14 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.1715G>A	p.Arg572Gln	missense_variant, splice_region_variant	Exon 14 of 17	1	NM_170604.3	ENSP00000479844.1	Q8TDF6-1
RASGRP4	ENST00000587738.2 link	c.1715G>A	p.Arg572Gln	missense_variant, splice_region_variant	Exon 14 of 17	5		ENSP00000465772.1	Q8TDF6-1
RASGRP4	ENST00000586305.5 link	c.1673G>A	p.Arg558Gln	missense_variant, splice_region_variant	Exon 14 of 17	1		ENSP00000467604.1	Q8TDF6-2
RASGRP4	ENST00000454404.6 link	c.1613G>A	p.Arg538Gln	missense_variant, splice_region_variant	Exon 14 of 17	1		ENSP00000416463.2	Q8TDF6-8
RASGRP4	ENST00000587753.5 link	c.1508G>A	p.Arg503Gln	missense_variant, splice_region_variant	Exon 14 of 17	1		ENSP00000468483.1	Q8TDF6-9
RASGRP4	ENST00000614135.4 link	c.1439G>A	p.Arg480Gln	missense_variant, splice_region_variant	Exon 13 of 16	5		ENSP00000479078.1	Q8TDF6-5
RASGRP4	ENST00000617966.4 link	c.1424G>A	p.Arg475Gln	missense_variant, splice_region_variant	Exon 12 of 15	5		ENSP00000479888.1	Q8TDF6-7
RASGRP4	ENST00000622174.4 link	c.1148G>A	p.Arg383Gln	missense_variant, splice_region_variant	Exon 11 of 14	5		ENSP00000484345.1	Q8TDF6-6
RASGRP4	ENST00000589358.5 link	n.1715G>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 14 of 18	5		ENSP00000465742.1	Q8TDF6-1
RASGRP4	ENST00000589474.5 link	n.1673G>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 14 of 18	5		ENSP00000466928.1	Q8TDF6-2

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000828

AC:

AN:

1448998

Hom.:

Cov.:

AF XY:

0.00000278

AC XY:

AN XY:

719532

show subpopulations

Gnomad4 AFR exome

AF:

0.0000302

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000119

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000723

Gnomad4 OTH exome

AF:

0.0000334

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152170

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74330

show subpopulations

Gnomad4 AFR

AF:

0.0000241

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:

0.0000147

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 17, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1715G>A (p.R572Q) alteration is located in exon 14 (coding exon 14) of the RASGRP4 gene. This alteration results from a G to A substitution at nucleotide position 1715, causing the arginine (R) at amino acid position 572 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

0.068

BayesDel_addAF

Benign

-0.0018

BayesDel_noAF

Benign

-0.24

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.039

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

Eigen

Benign

-0.27

Eigen_PC

Benign

-0.14

FATHMM_MKL

Benign

0.47

LIST_S2

Benign

0.84

.;.;.;T;D;.;T;D;D;D;D;.

M_CAP

Benign

0.036

MetaRNN

Benign

0.22

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

MetaSVM

Uncertain

0.065

MutationAssessor

Benign

-0.19

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

PrimateAI

Benign

0.24

PROVEAN

Benign

-2.0

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

REVEL

Benign

0.18

Sift

Benign

0.059

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

Sift4G

Uncertain

0.019

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

Polyphen

0.010

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

Vest4

0.23

MutPred

0.26

.;.;.;.;.;.;Gain of sheet (P = 0.0827);.;.;Gain of sheet (P = 0.0827);.;Gain of sheet (P = 0.0827);

MVP

0.82

MPC

0.35

ClinPred

0.63

GERP RS

2.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.10

gMVP

0.24

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00021

dbscSNV1_RF

Benign

0.20

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