rs766560217

Variant names:

• chr19-38412764-C-T
• rs766560217
• NM_170604.3:c.1588G>A

Variant summary

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

The NM_170604.3(RASGRP4):​c.1588G>A​(p.Ala530Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000687 in 1,456,486 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000069 (0 hom.)
• Consequence: RASGRP4 NM_170604.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.901

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=0.13243341).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RASGRP4	NM_170604.3	c.1588G>A	p.Ala530Thr	missense_variant	Exon 13 of 17	ENST00000615439.5	NP_733749.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RASGRP4	ENST00000615439.5	c.1588G>A	p.Ala530Thr	missense_variant	Exon 13 of 17	1	NM_170604.3	ENSP00000479844.1
RASGRP4	ENST00000587738.2	c.1588G>A	p.Ala530Thr	missense_variant	Exon 13 of 17	5		ENSP00000465772.1
RASGRP4	ENST00000586305.5	c.1546G>A	p.Ala516Thr	missense_variant	Exon 13 of 17	1		ENSP00000467604.1
RASGRP4	ENST00000454404.6	c.1486G>A	p.Ala496Thr	missense_variant	Exon 13 of 17	1		ENSP00000416463.2
RASGRP4	ENST00000587753.5	c.1381G>A	p.Ala461Thr	missense_variant	Exon 13 of 17	1		ENSP00000468483.1
RASGRP4	ENST00000614135.4	c.1312G>A	p.Ala438Thr	missense_variant	Exon 12 of 16	5		ENSP00000479078.1
RASGRP4	ENST00000617966.4	c.1297G>A	p.Ala433Thr	missense_variant	Exon 11 of 15	5		ENSP00000479888.1
RASGRP4	ENST00000622174.4	c.1021G>A	p.Ala341Thr	missense_variant	Exon 10 of 14	5		ENSP00000484345.1
RASGRP4	ENST00000589358.5	n.1588G>A		non_coding_transcript_exon_variant	Exon 13 of 18	5		ENSP00000465742.1
RASGRP4	ENST00000589474.5	n.1546G>A		non_coding_transcript_exon_variant	Exon 13 of 18	5		ENSP00000466928.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000687 AC: 10 AN: 1456486 Hom.: 0 Cov.: 32 AF XY: 0.00000967 AC XY: 7 AN XY: 724174

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000811

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000329 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000827 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 19, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1588G>A (p.A530T) alteration is located in exon 13 (coding exon 13) of the RASGRP4 gene. This alteration results from a G to A substitution at nucleotide position 1588, causing the alanine (A) at amino acid position 530 to be replaced by a threonine (T). 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	0.077
BayesDel_addAF	Uncertain	0.032	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.027	.;.;.;.;.;.;T;.;.;T;.;T
Eigen	Benign	0.0071
Eigen_PC	Benign	0.040
FATHMM_MKL	Benign	0.30	N
LIST_S2	Uncertain	0.95	.;.;.;D;D;.;D;D;D;D;D;.
M_CAP	Benign	0.040	D
MetaRNN	Benign	0.13	T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.22	D
MutationAssessor	Benign	1.4	.;.;.;.;.;.;.;.;.;L;.;L
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.3	.;.;.;.;.;.;.;N;N;.;N;.
REVEL	Uncertain	0.31
Sift	Uncertain	0.021	.;.;.;.;.;.;.;D;D;.;D;.
Sift4G	Benign	0.18	T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.88	P;.;.;.;.;.;.;.;.;D;.;D
Vest4		0.13
MutPred		0.39		.;.;.;.;.;.;Gain of helix (P = 0.062);.;.;Gain of helix (P = 0.062);.;Gain of helix (P = 0.062);
MVP		0.84
MPC		0.29
ClinPred		0.65	D
GERP RS		4.5
Varity_R		0.073
gMVP		0.43

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: rs766560217; hg19: chr19-38903404; COSMIC: COSV53040334; COSMIC: COSV53040334;