NM_170604.3:c.1715G>C

Variant names:

• chr19-38411347-C-G
• NM_170604.3:c.1715G>C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_170604.3(RASGRP4):​c.1715G>C​(p.Arg572Pro) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000207 in 1,448,998 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: RASGRP4 NM_170604.3 missense, splice_region
• Scores: Splicing: ADA: 0.0004374
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.161

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.849

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RASGRP4	NM_170604.3	c.1715G>C	p.Arg572Pro	missense_variant, splice_region_variant	Exon 14 of 17	ENST00000615439.5	NP_733749.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RASGRP4	ENST00000615439.5	c.1715G>C	p.Arg572Pro	missense_variant, splice_region_variant	Exon 14 of 17	1	NM_170604.3	ENSP00000479844.1
RASGRP4	ENST00000587738.2	c.1715G>C	p.Arg572Pro	missense_variant, splice_region_variant	Exon 14 of 17	5		ENSP00000465772.1
RASGRP4	ENST00000586305.5	c.1673G>C	p.Arg558Pro	missense_variant, splice_region_variant	Exon 14 of 17	1		ENSP00000467604.1
RASGRP4	ENST00000454404.6	c.1613G>C	p.Arg538Pro	missense_variant, splice_region_variant	Exon 14 of 17	1		ENSP00000416463.2
RASGRP4	ENST00000587753.5	c.1508G>C	p.Arg503Pro	missense_variant, splice_region_variant	Exon 14 of 17	1		ENSP00000468483.1
RASGRP4	ENST00000614135.4	c.1439G>C	p.Arg480Pro	missense_variant, splice_region_variant	Exon 13 of 16	5		ENSP00000479078.1
RASGRP4	ENST00000617966.4	c.1424G>C	p.Arg475Pro	missense_variant, splice_region_variant	Exon 12 of 15	5		ENSP00000479888.1
RASGRP4	ENST00000622174.4	c.1148G>C	p.Arg383Pro	missense_variant, splice_region_variant	Exon 11 of 14	5		ENSP00000484345.1
RASGRP4	ENST00000589358.5	n.1715G>C		splice_region_variant, non_coding_transcript_exon_variant	Exon 14 of 18	5		ENSP00000465742.1
RASGRP4	ENST00000589474.5	n.1673G>C		splice_region_variant, non_coding_transcript_exon_variant	Exon 14 of 18	5		ENSP00000466928.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000207 AC: 3 AN: 1448998 Hom.: 0 Cov.: 32 AF XY: 0.00000139 AC XY: 1 AN XY: 719532

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: 0.00000271

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.15	.;.;.;.;.;.;T;.;.;D;.;D
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.89	.;.;.;D;D;.;T;D;D;D;D;.
M_CAP	Pathogenic	0.44	D
MetaRNN	Pathogenic	0.85	D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.81	D
MutationAssessor	Uncertain	2.6	.;.;.;.;.;.;.;.;.;M;.;M
PrimateAI	Benign	0.28	T
PROVEAN	Pathogenic	-4.5	.;.;.;.;.;.;.;D;D;.;D;.
REVEL	Pathogenic	0.68
Sift	Uncertain	0.0010	.;.;.;.;.;.;.;D;D;.;D;.
Sift4G	Uncertain	0.0060	D;D;D;D;D;D;D;D;D;D;D;D
Polyphen		0.70	P;.;.;.;.;.;.;.;.;P;.;P
Vest4		0.61
MutPred		0.30		.;.;.;.;.;.;Gain of sheet (P = 0.0827);.;.;Gain of sheet (P = 0.0827);.;Gain of sheet (P = 0.0827);
MVP		0.80
MPC		1.1
ClinPred		0.98	D
GERP RS		2.4
Varity_R		0.72
gMVP		0.75

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00044
dbscSNV1_RF	Benign	0.31
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-38901987;