19-38415078-C-G

Variant names:

• chr19-38415078-C-G
• rs762299166
• NM_170604.3:c.1000G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_170604.3(RASGRP4):​c.1000G>C​(p.Ala334Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000069 in 1,448,894 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A334T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: RASGRP4 NM_170604.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0740
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20153326).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RASGRP4	NM_170604.3	c.1000G>C	p.Ala334Pro	missense_variant	Exon 9 of 17	ENST00000615439.5	NP_733749.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RASGRP4	ENST00000615439.5	c.1000G>C	p.Ala334Pro	missense_variant	Exon 9 of 17	1	NM_170604.3	ENSP00000479844.1
RASGRP4	ENST00000587738.2	c.1000G>C	p.Ala334Pro	missense_variant	Exon 9 of 17	5		ENSP00000465772.1
RASGRP4	ENST00000586305.5	c.958G>C	p.Ala320Pro	missense_variant	Exon 9 of 17	1		ENSP00000467604.1
RASGRP4	ENST00000454404.6	c.898G>C	p.Ala300Pro	missense_variant	Exon 9 of 17	1		ENSP00000416463.2
RASGRP4	ENST00000617966.4	c.709G>C	p.Ala237Pro	missense_variant	Exon 7 of 15	5		ENSP00000479888.1
RASGRP4	ENST00000589358.5	n.1000G>C		non_coding_transcript_exon_variant	Exon 9 of 18	5		ENSP00000465742.1
RASGRP4	ENST00000589474.5	n.958G>C		non_coding_transcript_exon_variant	Exon 9 of 18	5		ENSP00000466928.1
RASGRP4	ENST00000587753.5	c.955-162G>C		intron_variant	Intron 8 of 16	1		ENSP00000468483.1
RASGRP4	ENST00000614135.4	c.955-1604G>C		intron_variant	Intron 8 of 15	5		ENSP00000479078.1
RASGRP4	ENST00000622174.4	c.664-1604G>C		intron_variant	Intron 6 of 13	5		ENSP00000484345.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.90e-7 AC: 1 AN: 1448894 Hom.: 0 Cov.: 32 AF XY: 0.00000139 AC XY: 1 AN XY: 719426

African (AFR) AF: 0.00 AC: 0 AN: 33236

American (AMR) AF: 0.00 AC: 0 AN: 42762

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25810

East Asian (EAS) AF: 0.00 AC: 0 AN: 39224

South Asian (SAS) AF: 0.00 AC: 0 AN: 84698

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52048

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5256

European-Non Finnish (NFE) AF: 9.04e-7 AC: 1 AN: 1106066

Other (OTH) AF: 0.00 AC: 0 AN: 59794

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.48
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.12	.;.;.;T;.;T;T
Eigen	Benign	-0.13
Eigen_PC	Benign	-0.27
FATHMM_MKL	Benign	0.18	N
LIST_S2	Uncertain	0.89	.;D;.;D;D;D;.
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.20	T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	.;.;.;.;.;L;L
PhyloP100		-0.074
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-1.9	.;.;.;.;N;.;.
REVEL	Benign	0.18
Sift	Benign	0.052	.;.;.;.;T;.;.
Sift4G	Benign	0.26	T;T;T;T;T;T;T
Polyphen		0.99	D;.;.;.;.;D;D
Vest4		0.38
MutPred		0.53		.;.;.;Loss of MoRF binding (P = 0.0587);.;Loss of MoRF binding (P = 0.0587);Loss of MoRF binding (P = 0.0587);
MVP		0.28
MPC		1.1
ClinPred		0.56	D
GERP RS		2.5
Varity_R		0.88
gMVP		0.66
Mutation Taster		=67/33	polymorphism

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

Other links and lift over

dbSNP: rs762299166; hg19: chr19-38905718;