3-141487109-C-T

Position:

chr3-141487109-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_006506.5(RASA2):c.26C>T(p.Ala9Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00595 in 1,408,594 control chromosomes in the GnomAD database, including 32 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A9S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0041 ( 6 hom., cov: 32)

Exomes 𝑓: 0.0062 ( 26 hom. )

Consequence

RASA2
NM_006506.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -0.103

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 Benign. Variant got -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.004125297).

BP6

Variant 3-141487109-C-T is Benign according to our data. Variant chr3-141487109-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 929175.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-141487109-C-T is described in Lovd as [Benign].

BS2

High Homozygotes in GnomAd4 at 6 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
RASA2	NM_006506.5 linkuse as main transcript	c.26C>T	p.Ala9Val	missense_variant	1/24	ENST00000286364.9
RASA2	NM_001303246.3 linkuse as main transcript	c.26C>T	p.Ala9Val	missense_variant	1/25
RASA2	NM_001303245.3 linkuse as main transcript	c.26C>T	p.Ala9Val	missense_variant	1/24
RASA2	XM_047448652.1 linkuse as main transcript	c.26C>T	p.Ala9Val	missense_variant	1/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RASA2	ENST00000286364.9 linkuse as main transcript	c.26C>T	p.Ala9Val	missense_variant	1/24	1	NM_006506.5	P1	Q15283-2
RASA2	ENST00000515549.1 linkuse as main transcript	c.26C>T	p.Ala9Val	missense_variant, NMD_transcript_variant	1/5	4

Frequencies

GnomAD3 genomes

AF:

0.00416

AC:

626

AN:

150486

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00129

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00489

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.000802

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00706

Gnomad OTH

AF:

0.00435

GnomAD3 exomes

AF:

0.00405

AC:

370

AN:

91248

Hom.:

AF XY:

0.00433

AC XY:

223

AN XY:

51508

show subpopulations

Gnomad AFR exome

AF:

0.00112

Gnomad AMR exome

AF:

0.00163

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000933

Gnomad FIN exome

AF:

0.00223

Gnomad NFE exome

AF:

0.00876

Gnomad OTH exome

AF:

0.00274

GnomAD4 exome

AF:

0.00616

AC:

7752

AN:

1258000

Hom.:

Cov.:

AF XY:

0.00602

AC XY:

3730

AN XY:

620074

show subpopulations

Gnomad4 AFR exome

AF:

0.000815

Gnomad4 AMR exome

AF:

0.00201

Gnomad4 ASJ exome

AF:

0.000100

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000729

Gnomad4 FIN exome

AF:

0.00299

Gnomad4 NFE exome

AF:

0.00726

Gnomad4 OTH exome

AF:

0.00476

GnomAD4 genome

AF:

0.00414

AC:

624

AN:

150594

Hom.:

Cov.:

AF XY:

0.00392

AC XY:

288

AN XY:

73554

show subpopulations

Gnomad4 AFR

AF:

0.00128

Gnomad4 AMR

AF:

0.00489

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000829

Gnomad4 FIN

AF:

0.000802

Gnomad4 NFE

AF:

0.00706

Gnomad4 OTH

AF:

0.00431

Alfa

AF:

0.00571

Hom.:

Bravo

AF:

0.00417

ESP6500AA

AF:

0.00145

AC:

ESP6500EA

AF:

0.00265

AC:

ExAC

AF:

0.00238

AC:

246

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 30, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	RASA2: BS2 -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 01, 2023	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 26, 2019	Variant summary: RASA2 c.26C>T (p.Ala9Val) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0041 in 91248 control chromosomes in the gnomAD database, including 4 homozygotes. The observed variant frequency is approximately 811 fold of the estimated maximal expected allele frequency for a pathogenic variant in RASA2 causing Noonan Syndrome and Related Conditions phenotype (5e-06), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.26C>T in individuals affected with Noonan Syndrome and Related Conditions and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as benign. -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 09, 2022	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

RASA2-related disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 14, 2020

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.24

CADD

Benign

DANN

Benign

0.96

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.14

LIST_S2

Benign

0.57

T;T

MetaRNN

Benign

0.0041

T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.0

N;.

MutationTaster

Benign

1.0

N;N

PrimateAI

Pathogenic

0.81

PROVEAN

Benign

0.060

N;N

REVEL

Benign

0.059

Sift

Benign

0.55

T;T

Sift4G

Pathogenic

0.0

D;D

Vest4

0.29

MVP

0.55

MPC

0.34

ClinPred

0.034

GERP RS

1.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.0

gMVP

0.35

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