3-141487094-C-T

Position:

chr3-141487094-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_006506.5(RASA2):c.11C>T(p.Ala4Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000153 in 1,374,532 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. A4A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000040 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

RASA2
NM_006506.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 0.929

Variant links:

Genes affected

RASA2 (HGNC:9872): (RAS p21 protein activator 2) The protein encoded by this gene is member of the GAP1 family of GTPase-activating proteins. The gene product stimulates the GTPase activity of normal RAS p21 but not its oncogenic counterpart. Acting as a suppressor of RAS function, the protein enhances the weak intrinsic GTPase activity of RAS proteins resulting in the inactive GDP-bound form of RAS, thereby allowing control of cellular proliferation and differentiation. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2014]

RASA2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.34783757).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
RASA2	NM_006506.5 linkuse as main transcript	c.11C>T	p.Ala4Val	missense_variant	1/24	ENST00000286364.9
RASA2	NM_001303246.3 linkuse as main transcript	c.11C>T	p.Ala4Val	missense_variant	1/25
RASA2	NM_001303245.3 linkuse as main transcript	c.11C>T	p.Ala4Val	missense_variant	1/24
RASA2	XM_047448652.1 linkuse as main transcript	c.11C>T	p.Ala4Val	missense_variant	1/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RASA2	ENST00000286364.9 linkuse as main transcript	c.11C>T	p.Ala4Val	missense_variant	1/24	1	NM_006506.5	P1	Q15283-2
RASA2	ENST00000515549.1 linkuse as main transcript	c.11C>T	p.Ala4Val	missense_variant, NMD_transcript_variant	1/5	4

Frequencies

GnomAD3 genomes

AF:

0.0000399

AC:

AN:

150454

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000970

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000662

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000194

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

AF:

0.0000123

AC:

AN:

1224078

Hom.:

Cov.:

AF XY:

0.00000997

AC XY:

AN XY:

601536

show subpopulations

Gnomad4 AFR exome

AF:

0.000288

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000164

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000712

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000399

AC:

AN:

150454

Hom.:

Cov.:

AF XY:

0.0000545

AC XY:

AN XY:

73418

show subpopulations

Gnomad4 AFR

AF:

0.0000970

Gnomad4 AMR

AF:

0.0000662

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000194

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000567

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 27, 2022

The p.A4V variant (also known as c.11C>T), located in coding exon 1 of the RASA2 gene, results from a C to T substitution at nucleotide position 11. The alanine at codon 4 is replaced by valine, an amino acid with similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Feb 16, 2023

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 4 of the RASA2 protein (p.Ala4Val). This variant is present in population databases (no rsID available, gnomAD 0.06%). This variant has not been reported in the literature in individuals affected with RASA2-related conditions. ClinVar contains an entry for this variant (Variation ID: 1747076). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Uncertain

0.037

BayesDel_noAF

Benign

-0.18

CADD

Benign

DANN

Uncertain

1.0

Eigen

Benign

0.014

Eigen_PC

Benign

0.025

FATHMM_MKL

Benign

0.65

LIST_S2

Benign

0.60

T;T

M_CAP

Pathogenic

0.91

MetaRNN

Benign

0.35

T;T

MetaSVM

Benign

-0.77

MutationAssessor

Benign

0.0

N;.

MutationTaster

Benign

0.98

N;N

PrimateAI

Pathogenic

0.84

PROVEAN

Benign

-0.29

N;N

REVEL

Benign

0.18

Sift

Benign

0.032

D;D

Sift4G

Uncertain

0.045

D;D

Vest4

0.35

MutPred

0.32

Gain of catalytic residue at A4 (P = 0.0127);Gain of catalytic residue at A4 (P = 0.0127);

MVP

0.78

MPC

0.34

ClinPred

0.60

GERP RS

3.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.0

gMVP

0.36

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over