3-141487100-C-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_006506.5(RASA2):c.17C>T(p.Pro6Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00523 in 1,392,716 control chromosomes in the GnomAD database, including 26 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0034 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0055 ( 25 hom. )

Consequence

RASA2
NM_006506.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:7

Conservation

PhyloP100: -0.315

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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.004214376).

BP6

Variant 3-141487100-C-T is Benign according to our data. Variant chr3-141487100-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 218684.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=5, Likely_benign=1}.

BS2

High Homozygotes in GnomAdExome4 at 25 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RASA2	NM_006506.5 link	c.17C>T	p.Pro6Leu	missense_variant	Exon 1 of 24	ENST00000286364.9	NP_006497.2	Q15283-2
RASA2	NM_001303246.3 link	c.17C>T	p.Pro6Leu	missense_variant	Exon 1 of 25		NP_001290175.1	Q15283
RASA2	NM_001303245.3 link	c.17C>T	p.Pro6Leu	missense_variant	Exon 1 of 24		NP_001290174.1	Q15283-1
RASA2	XM_047448652.1 link	c.17C>T	p.Pro6Leu	missense_variant	Exon 1 of 17		XP_047304608.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RASA2	ENST00000286364.9 link	c.17C>T	p.Pro6Leu	missense_variant	Exon 1 of 24	1	NM_006506.5	ENSP00000286364.3		Q15283-2
RASA2	ENST00000515549.1 link	n.17C>T		non_coding_transcript_exon_variant	Exon 1 of 5	4		ENSP00000424293.1		D6RBA9

Frequencies

GnomAD3 genomes

AF:

0.00338

AC:

509

AN:

150574

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000920

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00231

Gnomad ASJ

AF:

0.000290

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.000805

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00613

Gnomad OTH

AF:

0.00290

GnomAD3 exomes

AF:

0.00357

AC:

281

AN:

78770

Hom.:

AF XY:

0.00317

AC XY:

141

AN XY:

44512

show subpopulations

Gnomad AFR exome

AF:

0.000897

Gnomad AMR exome

AF:

0.00250

Gnomad ASJ exome

AF:

0.000191

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00132

Gnomad FIN exome

AF:

0.000727

Gnomad NFE exome

AF:

0.00784

Gnomad OTH exome

AF:

0.00460

GnomAD4 exome

AF:

0.00545

AC:

6773

AN:

1242034

Hom.:

Cov.:

AF XY:

0.00532

AC XY:

3252

AN XY:

611394

show subpopulations

Gnomad4 AFR exome

AF:

0.000716

Gnomad4 AMR exome

AF:

0.00250

Gnomad4 ASJ exome

AF:

0.000105

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00192

Gnomad4 FIN exome

AF:

0.00101

Gnomad4 NFE exome

AF:

0.00634

Gnomad4 OTH exome

AF:

0.00503

GnomAD4 genome

AF:

0.00337

AC:

508

AN:

150682

Hom.:

Cov.:

AF XY:

0.00293

AC XY:

216

AN XY:

73610

show subpopulations

Gnomad4 AFR

AF:

0.000918

Gnomad4 AMR

AF:

0.00231

Gnomad4 ASJ

AF:

0.000290

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00124

Gnomad4 FIN

AF:

0.000805

Gnomad4 NFE

AF:

0.00613

Gnomad4 OTH

AF:

0.00287

Alfa

AF:

0.00476

Hom.:

Bravo

AF:

0.00322

ESP6500AA

AF:

0.000741

AC:

ESP6500EA

AF:

0.00223

AC:

ExAC

AF:

0.00152

AC:

149

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:7

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:4

May 15, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 06, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

RASA2: BS1, BS2 -

not specified

Uncertain:1Benign:2

Jun 18, 2015

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 26, 2019

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: RASA2 c.17C>T (p.Pro6Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0036 in 78770 control chromosomes in the gnomAD database, including 2 homozygotes. The observed variant frequency is approximately 713 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.17C>T in individuals affected with Noonan Syndrome and Related Conditions and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as benign. -

Sep 24, 2022

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Oct 26, 2020

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

-0.40

BayesDel_noAF

Benign

-0.34

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.25

.;T

Eigen

Benign

-0.65

Eigen_PC

Benign

-0.62

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.45

T;T

MetaRNN

Benign

0.0042

T;T

MetaSVM

Benign

-0.85

MutationAssessor

Benign

0.0

N;.

PrimateAI

Pathogenic

0.79

PROVEAN

Benign

-0.73

N;N

REVEL

Benign

0.11

Sift

Benign

0.18

T;T

Sift4G

Benign

0.24

T;T

Vest4

0.10

MVP

0.74

MPC

0.35

ClinPred

0.047

GERP RS

1.6

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