19-38411126-T-C

Variant names:

• chr19-38411126-T-C
• rs1971234067
• NM_170604.3:c.1841A>G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_170604.3(RASGRP4):​c.1841A>G​(p.His614Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 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: not found (cov: 32)
• Consequence: RASGRP4 NM_170604.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.339

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.059869558).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RASGRP4	NM_170604.3	c.1841A>G	p.His614Arg	missense_variant	Exon 15 of 17	ENST00000615439.5	NP_733749.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RASGRP4	ENST00000615439.5	c.1841A>G	p.His614Arg	missense_variant	Exon 15 of 17	1	NM_170604.3	ENSP00000479844.1
RASGRP4	ENST00000587738.2	c.1841A>G	p.His614Arg	missense_variant	Exon 15 of 17	5		ENSP00000465772.1
RASGRP4	ENST00000586305.5	c.1799A>G	p.His600Arg	missense_variant	Exon 15 of 17	1		ENSP00000467604.1
RASGRP4	ENST00000454404.6	c.1739A>G	p.His580Arg	missense_variant	Exon 15 of 17	1		ENSP00000416463.2
RASGRP4	ENST00000587753.5	c.1634A>G	p.His545Arg	missense_variant	Exon 15 of 17	1		ENSP00000468483.1
RASGRP4	ENST00000614135.4	c.1565A>G	p.His522Arg	missense_variant	Exon 14 of 16	5		ENSP00000479078.1
RASGRP4	ENST00000617966.4	c.1550A>G	p.His517Arg	missense_variant	Exon 13 of 15	5		ENSP00000479888.1
RASGRP4	ENST00000622174.4	c.1274A>G	p.His425Arg	missense_variant	Exon 12 of 14	5		ENSP00000484345.1
RASGRP4	ENST00000589358.5	n.1841A>G		non_coding_transcript_exon_variant	Exon 15 of 18	5		ENSP00000465742.1
RASGRP4	ENST00000589474.5	n.1799A>G		non_coding_transcript_exon_variant	Exon 15 of 18	5		ENSP00000466928.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 11, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1841A>G (p.H614R) alteration is located in exon 15 (coding exon 15) of the RASGRP4 gene. This alteration results from a A to G substitution at nucleotide position 1841, causing the histidine (H) at amino acid position 614 to be replaced by an arginine (R). 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	0.059
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	5.4
DANN	Benign	0.69
DEOGEN2	Benign	0.018	.;.;.;.;.;.;.;.;T;.;T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.43	.;.;.;T;T;.;T;T;T;T;.
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.060	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.46	.;.;.;.;.;.;.;.;N;.;N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.9	.;.;.;.;.;.;N;N;.;N;.
REVEL	Benign	0.10
Sift	Benign	0.040	.;.;.;.;.;.;D;T;.;T;.
Sift4G	Benign	0.57	T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.0	B;.;.;.;.;.;.;.;B;.;B
Vest4		0.15
MutPred		0.21		.;.;.;.;.;.;.;.;Gain of stability (P = 0.0811);.;Gain of stability (P = 0.0811);
MVP		0.31
MPC		0.34
ClinPred		0.075	T
GERP RS		-2.5
Varity_R		0.091
gMVP		0.20

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

Other links and lift over

dbSNP: rs1971234067; hg19: chr19-38901766;