chr19-38422124-A-C

Variant names:

• chr19-38422124-A-C
• NM_170604.3:c.53T>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_170604.3(RASGRP4):​c.53T>G​(p.Ile18Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,118 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I18T) has been classified as Likely benign.

• 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: 2.84

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09135154).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RASGRP4	NM_170604.3	c.53T>G	p.Ile18Arg	missense_variant	Exon 2 of 17	ENST00000615439.5	NP_733749.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RASGRP4	ENST00000615439.5	c.53T>G	p.Ile18Arg	missense_variant	Exon 2 of 17	1	NM_170604.3	ENSP00000479844.1
RASGRP4	ENST00000587738.2	c.53T>G	p.Ile18Arg	missense_variant	Exon 2 of 17	5		ENSP00000465772.1
RASGRP4	ENST00000586305.5	c.53T>G	p.Ile18Arg	missense_variant	Exon 2 of 17	1		ENSP00000467604.1
RASGRP4	ENST00000454404.6	c.53T>G	p.Ile18Arg	missense_variant	Exon 2 of 17	1		ENSP00000416463.2
RASGRP4	ENST00000587753.5	c.53T>G	p.Ile18Arg	missense_variant	Exon 2 of 17	1		ENSP00000468483.1
RASGRP4	ENST00000614135.4	c.53T>G	p.Ile18Arg	missense_variant	Exon 2 of 16	5		ENSP00000479078.1
RASGRP4	ENST00000617966.4	c.53T>G	p.Ile18Arg	missense_variant	Exon 2 of 15	5		ENSP00000479888.1
RASGRP4	ENST00000622174.4	c.53T>G	p.Ile18Arg	missense_variant	Exon 2 of 14	5		ENSP00000484345.1
RASGRP4	ENST00000589358.5	n.53T>G		non_coding_transcript_exon_variant	Exon 2 of 18	5		ENSP00000465742.1
RASGRP4	ENST00000589474.5	n.53T>G		non_coding_transcript_exon_variant	Exon 2 of 18	5		ENSP00000466928.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459118 Hom.: 0 Cov.: 38 AF XY: 0.00000138 AC XY: 1 AN XY: 725852

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: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	16
DANN	Benign	0.88
DEOGEN2	Benign	0.0085	.;.;.;.;.;.;T;.;.;T;.;T
Eigen	Benign	-0.86
Eigen_PC	Benign	-0.80
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.51	.;.;.;T;T;.;T;T;T;T;T;.
M_CAP	Benign	0.0082	T
MetaRNN	Benign	0.091	T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N;N;N;N;N;N;.;N;N;N;N;N
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.55	.;.;.;.;N;.;.;N;N;.;N;.
REVEL	Benign	0.061
Sift	Uncertain	0.016	.;.;.;.;D;.;.;D;D;.;D;.
Sift4G	Benign	0.098	T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.0	B;.;.;.;.;.;.;.;.;B;.;B
Vest4		0.18
MutPred		0.34		Gain of methylation at I18 (P = 0.0051);Gain of methylation at I18 (P = 0.0051);Gain of methylation at I18 (P = 0.0051);Gain of methylation at I18 (P = 0.0051);Gain of methylation at I18 (P = 0.0051);Gain of methylation at I18 (P = 0.0051);Gain of methylation at I18 (P = 0.0051);Gain of methylation at I18 (P = 0.0051);Gain of methylation at I18 (P = 0.0051);Gain of methylation at I18 (P = 0.0051);Gain of methylation at I18 (P = 0.0051);Gain of methylation at I18 (P = 0.0051);
MVP		0.16
MPC		0.51
ClinPred		0.092	T
GERP RS		4.1
Varity_R		0.080
gMVP		0.21

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-38912764;