19-38412988-C-T

Variant names:

• chr19-38412988-C-T
• rs775615920
• NM_170604.3:c.1478G>A

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.1478G>A​(p.Arg493Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,461,704 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: RASGRP4 NM_170604.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.25
• Publications: 1 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=0.18177128).

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.1478G>A	p.Arg493Gln	missense	Exon 12 of 17	NP_733749.1	Q8TDF6-1
	RASGRP4	NM_001146202.2		c.1436G>A	p.Arg479Gln	missense	Exon 12 of 17	NP_001139674.1	Q8TDF6-2
	RASGRP4	NM_001146205.2		c.1376G>A	p.Arg459Gln	missense	Exon 12 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.1478G>A	p.Arg493Gln	missense	Exon 12 of 17	ENSP00000479844.1	Q8TDF6-1
	RASGRP4	ENST00000587738.2	TSL:5	c.1478G>A	p.Arg493Gln	missense	Exon 12 of 17	ENSP00000465772.1	Q8TDF6-1
	RASGRP4	ENST00000586305.5	TSL:1	c.1436G>A	p.Arg479Gln	missense	Exon 12 of 17	ENSP00000467604.1	Q8TDF6-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000802 AC: 2 AN: 249278 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000885

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461704 Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5 AN XY: 727138

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.0000224 AC: 1 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000720 AC: 8 AN: 1111866

Other (OTH) AF: 0.00 AC: 0 AN: 60374

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000468 Hom.: 0

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.010	T
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.26
FATHMM_MKL	Benign	0.43	N
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-0.71	T
MutationAssessor	Benign	-0.20	N
PhyloP100		1.2
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.047
Sift	Benign	0.37	T
Sift4G	Benign	0.51	T
Polyphen		0.77	P
Vest4		0.37
MutPred		0.34		Gain of helix (P = 0.0425)
MVP		0.66
MPC		0.57
ClinPred		0.48	T
GERP RS		3.7
Varity_R		0.086
gMVP		0.23
Mutation Taster		=83/17	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: rs775615920; hg19: chr19-38903628; COSMIC: COSV99384984; COSMIC: COSV99384984;