chr19-38410968-G-C

Variant names:

• chr19-38410968-G-C
• rs755325515
• NM_170604.3:c.1883C>G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_170604.3(RASGRP4):​c.1883C>G​(p.Ser628Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000276 in 1,449,928 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 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)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: RASGRP4 NM_170604.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.83

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27219382).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RASGRP4	NM_170604.3	c.1883C>G	p.Ser628Cys	missense_variant	Exon 16 of 17	ENST00000615439.5	NP_733749.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RASGRP4	ENST00000615439.5	c.1883C>G	p.Ser628Cys	missense_variant	Exon 16 of 17	1	NM_170604.3	ENSP00000479844.1
RASGRP4	ENST00000587738.2	c.1883C>G	p.Ser628Cys	missense_variant	Exon 16 of 17	5		ENSP00000465772.1
RASGRP4	ENST00000586305.5	c.1841C>G	p.Ser614Cys	missense_variant	Exon 16 of 17	1		ENSP00000467604.1
RASGRP4	ENST00000454404.6	c.1781C>G	p.Ser594Cys	missense_variant	Exon 16 of 17	1		ENSP00000416463.2
RASGRP4	ENST00000587753.5	c.1676C>G	p.Ser559Cys	missense_variant	Exon 16 of 17	1		ENSP00000468483.1
RASGRP4	ENST00000614135.4	c.1607C>G	p.Ser536Cys	missense_variant	Exon 15 of 16	5		ENSP00000479078.1
RASGRP4	ENST00000617966.4	c.1592C>G	p.Ser531Cys	missense_variant	Exon 14 of 15	5		ENSP00000479888.1
RASGRP4	ENST00000622174.4	c.1316C>G	p.Ser439Cys	missense_variant	Exon 13 of 14	5		ENSP00000484345.1
RASGRP4	ENST00000589358.5	n.1883C>G		non_coding_transcript_exon_variant	Exon 16 of 18	5		ENSP00000465742.1
RASGRP4	ENST00000589474.5	n.1841C>G		non_coding_transcript_exon_variant	Exon 16 of 18	5		ENSP00000466928.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000883 AC: 2 AN: 226382 Hom.: 0 AF XY: 0.00000817 AC XY: 1 AN XY: 122448

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: 0.00000983

Gnomad OTH exome AF: 0.000179

GnomAD4 exome AF: 0.00000276 AC: 4 AN: 1449928 Hom.: 0 Cov.: 31 AF XY: 0.00000417 AC XY: 3 AN XY: 720036

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: 0.00000361

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000828 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.025	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.037	.;.;.;.;.;.;.;.;T;.;T
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.83	.;.;.;T;T;.;T;T;T;T;.
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.27	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.35	T
MutationAssessor	Benign	0.90	.;.;.;.;.;.;.;.;L;.;L
PrimateAI	Benign	0.34	T
PROVEAN	Uncertain	-2.5	.;.;.;.;.;.;D;D;.;N;.
REVEL	Benign	0.28
Sift	Uncertain	0.0020	.;.;.;.;.;.;D;D;.;D;.
Sift4G	Uncertain	0.054	T;T;T;T;T;D;D;T;T;T;T
Polyphen		0.91	P;.;.;.;.;.;.;.;P;.;P
Vest4		0.19
MutPred		0.28		.;.;.;.;.;.;.;.;Gain of catalytic residue at L629 (P = 0.0235);.;Gain of catalytic residue at L629 (P = 0.0235);
MVP		0.80
MPC		0.28
ClinPred		0.68	D
GERP RS		5.4
Varity_R		0.29
gMVP		0.47

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: rs755325515; hg19: chr19-38901608;