rs2230917

Positions:

chr19-49635738-C-G

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6

The NM_006270.5(RRAS):c.568G>C(p.Val190Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000219 in 1,570,188 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0012 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

RRAS
NM_006270.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3

Conservation

PhyloP100: 3.59

Variant links:

Genes affected

RRAS (HGNC:10447): (RAS related) The protein encoded by this gene is a small GTPase involved in diverse processes including angiogenesis, vascular homeostasis and regeneration, cell adhesion, and neuronal axon guidance. Mutations in this gene are found in many invasive cancers. [provided by RefSeq, Jul 2015]

RRAS links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.012400717).

BP6

Variant 19-49635738-C-G is Benign according to our data. Variant chr19-49635738-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 527794.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RRAS	NM_006270.5 linkuse as main transcript	c.568G>C	p.Val190Leu	missense_variant	5/6	ENST00000246792.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RRAS	ENST00000246792.4 linkuse as main transcript	c.568G>C	p.Val190Leu	missense_variant	5/6	1	NM_006270.5	P1

Frequencies

GnomAD3 genomes

AF:

0.00122

AC:

185

AN:

152112

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00425

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000458

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000308

AC:

AN:

243620

Hom.:

AF XY:

0.000182

AC XY:

AN XY:

131936

show subpopulations

Gnomad AFR exome

AF:

0.00457

Gnomad AMR exome

AF:

0.0000611

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000901

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000112

AC:

159

AN:

1417958

Hom.:

Cov.:

AF XY:

0.0000871

AC XY:

AN XY:

700596

show subpopulations

Gnomad4 AFR exome

AF:

0.00446

Gnomad4 AMR exome

AF:

0.0000925

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.27e-7

Gnomad4 OTH exome

AF:

0.000155

GnomAD4 genome

AF:

0.00122

AC:

185

AN:

152230

Hom.:

Cov.:

AF XY:

0.00102

AC XY:

AN XY:

74436

show subpopulations

Gnomad4 AFR

AF:

0.00424

Gnomad4 AMR

AF:

0.000458

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000291

Hom.:

Bravo

AF:

0.00144

ESP6500AA

AF:

0.00613

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000379

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 14, 2021	The p.V190L variant (also known as c.568G>C), located in coding exon 5 of the RRAS gene, results from a G to C substitution at nucleotide position 568. The valine at codon 190 is replaced by leucine, an amino acid with highly 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. -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 13, 2020	Variant summary: RRAS c.568G>C (p.Val190Leu) results in a 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 0.00041 in 274984 control chromosomes, predominantly at a frequency of 0.0045 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 1800 fold of the estimated maximal expected allele frequency for a pathogenic variant in RRAS causing Noonan Syndrome And Related Conditions phenotype (2.5e-06), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. To our knowledge, no occurrence of c.568G>C in individuals affected with Noonan Syndrome And Related Conditions and no experimental evidence demonstrating its impact on protein function have been reported. One ClinVar submitter (evaluation after 2014) cites the variant as likely benign. Based on the evidence outlined above, the variant was classified as likely benign. -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Sep 08, 2020

- -

Noonan syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.63

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.22

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.59

Eigen

Benign

-0.31

Eigen_PC

Benign

-0.19

FATHMM_MKL

Uncertain

0.84

LIST_S2

Uncertain

0.96

M_CAP

Uncertain

0.096

MetaRNN

Benign

0.012

MetaSVM

Benign

-0.81

MutationAssessor

Benign

1.1

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.72

PROVEAN

Benign

-1.7

REVEL

Uncertain

0.33

Sift

Uncertain

0.019

Sift4G

Uncertain

0.0080

Polyphen

0.33

Vest4

0.46

MVP

0.89

MPC

0.44

ClinPred

0.016

GERP RS

3.6

Varity_R

0.39

gMVP

0.51

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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