2-33558917-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001139488.2(RASGRP3):c.1951G>T(p.Ala651Ser) 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 benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RASGRP3 NM_001139488.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.68

Genes affected

RASGRP3 (HGNC:14545): (RAS guanyl releasing protein 3) The protein encoded by this gene is a guanine nucleotide exchange factor that activates the oncogenes HRAS and RAP1A. Defects in this gene have been associated with systemic lupus erythematosus and several cancers. [provided by RefSeq, Mar 2017]

RASGRP3-AS1 (HGNC:):

FAM98A (HGNC:24520): (family with sequence similarity 98 member A) Enables protein methyltransferase activity. Involved in positive regulation of cell population proliferation; positive regulation of gene expression; and protein methylation. Predicted to be part of tRNA-splicing ligase complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2925779).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RASGRP3	NM_001139488.2	c.1951G>T	p.Ala651Ser	missense_variant	17/18	ENST00000403687.8
RASGRP3-AS1	NR_146505.1	n.2497-3603C>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RASGRP3	ENST00000403687.8	c.1951G>T	p.Ala651Ser	missense_variant	17/18	1	NM_001139488.2	P5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

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 22, 2023

The c.1951G>T (p.A651S) alteration is located in exon 17 (coding exon 15) of the RASGRP3 gene. This alteration results from a G to T substitution at nucleotide position 1951, causing the alanine (A) at amino acid position 651 to be replaced by a serine (S). 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	0.14
BayesDel_addAF	Uncertain	0.029	T
BayesDel_noAF	Benign	-0.20
Cadd	Uncertain	24
Dann	Uncertain	0.99
DEOGEN2	Benign	0.21	T;T;.
Eigen	Benign	0.065
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.94	D
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.29	T;T;T
MetaSVM	Benign	-0.62	T
MutationAssessor	Benign	1.1	L;L;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-0.89	N;N;N
REVEL	Uncertain	0.33
Sift	Uncertain	0.025	D;D;D
Sift4G	Uncertain	0.051	T;T;T
Polyphen		0.093	B;B;.
Vest4		0.40
MutPred		0.14		Gain of phosphorylation at A651 (P = 0.0841);Gain of phosphorylation at A651 (P = 0.0841);.;
MVP		0.72
MPC		0.10
ClinPred		0.70	D
GERP RS		5.6
Varity_R		0.10
gMVP		0.34

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: rs1676324266; hg19: chr2-33783984;