2-33522043-C-T

Position:

• chr2-33522043-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001139488.2(RASGRP3):​c.457C>T​(p.Pro153Ser) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: RASGRP3 NM_001139488.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.91

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.822

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RASGRP3	NM_001139488.2	c.457C>T	p.Pro153Ser	missense_variant	7/18	ENST00000403687.8	NP_001132960.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RASGRP3	ENST00000403687.8	c.457C>T	p.Pro153Ser	missense_variant	7/18	1	NM_001139488.2	ENSP00000384192.3
RASGRP3	ENST00000402538.7	c.457C>T	p.Pro153Ser	missense_variant	8/19	1		ENSP00000385886.3
RASGRP3	ENST00000407811.5	c.457C>T	p.Pro153Ser	missense_variant	6/17	1		ENSP00000383917.1
RASGRP3	ENST00000437184.5	c.457C>T	p.Pro153Ser	missense_variant	7/7	5		ENSP00000393866.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

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

Oct 08, 2024

The c.457C>T (p.P153S) alteration is located in exon 7 (coding exon 5) of the RASGRP3 gene. This alteration results from a C to T substitution at nucleotide position 457, causing the proline (P) at amino acid position 153 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	Uncertain	0.44
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.63	D;.;D;.
Eigen	Uncertain	0.65
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.91	.;D;D;D
M_CAP	Benign	0.047	D
MetaRNN	Pathogenic	0.82	D;D;D;D
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.8	L;.;L;L
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-4.9	D;D;D;D
REVEL	Uncertain	0.32
Sift	Benign	0.050	D;T;D;T
Sift4G	Benign	0.11	T;T;T;T
Polyphen		0.75	P;.;P;.
Vest4		0.84
MutPred		0.66		Loss of loop (P = 0.0986);Loss of loop (P = 0.0986);Loss of loop (P = 0.0986);Loss of loop (P = 0.0986);
MVP		0.84
MPC		0.43
ClinPred		0.98	D
GERP RS		5.8
Varity_R		0.42
gMVP		0.78

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: rs750271899; hg19: chr2-33747110;