19-38414853-G-A

Position:

• chr19-38414853-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_170604.3(RASGRP4):​c.1225C>T​(p.Leu409Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: RASGRP4 NM_170604.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.97

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.861

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RASGRP4	NM_170604.3	c.1225C>T	p.Leu409Phe	missense_variant	9/17	ENST00000615439.5	NP_733749.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RASGRP4	ENST00000615439.5	c.1225C>T	p.Leu409Phe	missense_variant	9/17	1	NM_170604.3	ENSP00000479844	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 21, 2024

The c.1225C>T (p.L409F) alteration is located in exon 9 (coding exon 9) of the RASGRP4 gene. This alteration results from a C to T substitution at nucleotide position 1225, causing the leucine (L) at amino acid position 409 to be replaced by a phenylalanine (F). 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	Pathogenic	0.65
BayesDel_addAF	Uncertain	0.084	D
BayesDel_noAF	Benign	-0.12
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.22	.;.;.;.;T;.;T;T
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	.;D;D;.;D;D;D;.
M_CAP	Uncertain	0.096	D
MetaRNN	Pathogenic	0.86	D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.23	D
MutationAssessor	Uncertain	2.4	.;.;.;.;.;.;M;M
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-3.7	.;.;.;.;.;D;.;.
REVEL	Uncertain	0.52
Sift	Uncertain	0.0010	.;.;.;.;.;D;.;.
Sift4G	Uncertain	0.0050	D;D;D;D;D;D;D;D
Polyphen		1.0	D;.;.;.;.;.;D;D
Vest4		0.79
MutPred		0.67		.;.;.;.;Loss of stability (P = 0.0468);.;Loss of stability (P = 0.0468);Loss of stability (P = 0.0468);
MVP		0.76
MPC		1.0
ClinPred		0.99	D
GERP RS		4.9
Varity_R		0.59
gMVP		0.68

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: chr19-38905493;