19-38412764-C-A

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_170604.3(RASGRP4):​c.1588G>T​(p.Ala530Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,456,486 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 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. A530T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: RASGRP4 NM_170604.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.901
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.04708749).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_170604.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RASGRP4	NM_170604.3	MANE Select	c.1588G>T	p.Ala530Ser	missense	Exon 13 of 17	NP_733749.1	Q8TDF6-1
	RASGRP4	NM_001146202.2		c.1546G>T	p.Ala516Ser	missense	Exon 13 of 17	NP_001139674.1	Q8TDF6-2
	RASGRP4	NM_001146205.2		c.1486G>T	p.Ala496Ser	missense	Exon 13 of 17	NP_001139677.1	Q8TDF6-8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RASGRP4	ENST00000615439.5	TSL:1 MANE Select	c.1588G>T	p.Ala530Ser	missense	Exon 13 of 17	ENSP00000479844.1	Q8TDF6-1
	RASGRP4	ENST00000587738.2	TSL:5	c.1588G>T	p.Ala530Ser	missense	Exon 13 of 17	ENSP00000465772.1	Q8TDF6-1
	RASGRP4	ENST00000586305.5	TSL:1	c.1546G>T	p.Ala516Ser	missense	Exon 13 of 17	ENSP00000467604.1	Q8TDF6-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1456486 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 724174

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33380

American (AMR) AF: 0.0000230 AC: 1 AN: 43452

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25992

East Asian (EAS) AF: 0.00 AC: 0 AN: 39514

South Asian (SAS) AF: 0.00 AC: 0 AN: 85552

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53062

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1109566

Other (OTH) AF: 0.00 AC: 0 AN: 60210

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.055	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	15
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0059	T
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.44
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.037	D
MetaRNN	Benign	0.047	T
MetaSVM	Benign	-0.47	T
MutationAssessor	Benign	0.070	N
PhyloP100		0.90
PrimateAI	Uncertain	0.48	T
PROVEAN	Benign	0.17	N
REVEL	Benign	0.21
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.018	B
Vest4		0.12
MutPred		0.41		Gain of phosphorylation at A530 (P = 0.0524)
MVP		0.72
MPC		0.29
ClinPred		0.80	D
GERP RS		4.5
Varity_R		0.068
gMVP		0.36
Mutation Taster		=79/21	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

dbSNP: rs766560217; hg19: chr19-38903404;