19-38410048-C-T

Variant names:

• chr19-38410048-C-T
• rs530924409
• NM_170604.3:c.2014G>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.2014G>A​(p.Asp672Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000132 in 152,090 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 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. D672H) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.000013 (0 hom., cov: 31)
• Consequence: RASGRP4 NM_170604.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.496
• 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=0.06939012).

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.2014G>A	p.Asp672Asn	missense	Exon 17 of 17	NP_733749.1	Q8TDF6-1
	RASGRP4	NM_001146202.2		c.1972G>A	p.Asp658Asn	missense	Exon 17 of 17	NP_001139674.1	Q8TDF6-2
	RASGRP4	NM_001146205.2		c.1912G>A	p.Asp638Asn	missense	Exon 17 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.2014G>A	p.Asp672Asn	missense	Exon 17 of 17	ENSP00000479844.1	Q8TDF6-1
	RASGRP4	ENST00000587738.2	TSL:5	c.2014G>A	p.Asp672Asn	missense	Exon 17 of 17	ENSP00000465772.1	Q8TDF6-1
	RASGRP4	ENST00000586305.5	TSL:1	c.1972G>A	p.Asp658Asn	missense	Exon 17 of 17	ENSP00000467604.1	Q8TDF6-2

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 152090 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 29

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 152090 Hom.: 0 Cov.: 31 AF XY: 0.0000269 AC XY: 2 AN XY: 74288

African (AFR) AF: 0.0000483 AC: 2 AN: 41414

American (AMR) AF: 0.00 AC: 0 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68016

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000371 Hom.: 0

Bravo AF: 0.0000227

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	0.49
DANN	Benign	0.95
DEOGEN2	Benign	0.0055	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.0067	N
LIST_S2	Benign	0.45	T
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.069	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-0.26	N
PhyloP100		-0.50
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.57	N
REVEL	Benign	0.21
Sift	Benign	0.17	T
Sift4G	Benign	0.45	T
Polyphen		0.0	B
Vest4		0.073
MVP		0.40
MPC		0.28
ClinPred		0.052	T
GERP RS		-3.2
Varity_R		0.039
gMVP		0.12
Mutation Taster		=99/1	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: rs530924409; hg19: chr19-38900688;