2-33524038-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001139488.2(RASGRP3):c.676A>G(p.Ile226Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: RASGRP3 NM_001139488.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.99

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RASGRP3	NM_001139488.2	c.676A>G	p.Ile226Val	missense_variant	8/18	ENST00000403687.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RASGRP3	ENST00000403687.8	c.676A>G	p.Ile226Val	missense_variant	8/18	1	NM_001139488.2	P5
RASGRP3	ENST00000402538.7	c.676A>G	p.Ile226Val	missense_variant	9/19	1		P5
RASGRP3	ENST00000407811.5	c.676A>G	p.Ile226Val	missense_variant	7/17	1		A1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

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 05, 2024

The c.676A>G (p.I226V) alteration is located in exon 8 (coding exon 6) of the RASGRP3 gene. This alteration results from a A to G substitution at nucleotide position 676, causing the isoleucine (I) at amino acid position 226 to be replaced by a valine (V). 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	0.11
BayesDel_addAF	Benign	-0.046	T
BayesDel_noAF	Benign	-0.30
Cadd	Uncertain	23
Dann	Uncertain	1.0
DEOGEN2	Benign	0.24	T;T;.
Eigen	Benign	0.17
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.95	D
M_CAP	Benign	0.0080	T
MetaRNN	Uncertain	0.62	D;D;D
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.51	N;N;N
MutationTaster	Benign	0.99	D;D;D
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-0.34	N;N;N
REVEL	Benign	0.16
Sift	Benign	0.35	T;T;T
Sift4G	Benign	0.17	T;T;T
Polyphen		0.41	B;B;.
Vest4		0.60
MutPred		0.66		Gain of MoRF binding (P = 0.1225);Gain of MoRF binding (P = 0.1225);Gain of MoRF binding (P = 0.1225);
MVP		0.76
MPC		0.50
ClinPred		0.82	D
GERP RS		5.5
Varity_R		0.096
gMVP		0.36

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-33749105;