Variant 19-49635587-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The ENST00000246792.4(RRAS):c.646G>A(p.Val216Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000222 in 1,443,756 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000040 ( 1 hom., cov: 31)

Exomes 𝑓: 0.000020 ( 0 hom. )

Consequence

RRAS
ENST00000246792.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.129

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 -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.051285833).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RRAS	NM_006270.5 linkuse as main transcript	c.646G>A	p.Val216Ile	missense_variant	6/6	ENST00000246792.4	NP_006261.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RRAS	ENST00000246792.4 linkuse as main transcript	c.646G>A	p.Val216Ile	missense_variant	6/6	1	NM_006270.5	ENSP00000246792	P1

Frequencies

GnomAD3 genomes

AF:

0.0000396

AC:

AN:

151646

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000736

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000450

AC:

AN:

155500

Hom.:

AF XY:

0.0000608

AC XY:

AN XY:

82174

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000122

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000835

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000504

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000201

AC:

AN:

1292110

Hom.:

Cov.:

AF XY:

0.0000238

AC XY:

AN XY:

630012

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000399

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000576

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000215

Gnomad4 OTH exome

AF:

0.0000191

GnomAD4 genome

AF:

0.0000396

AC:

AN:

151646

Hom.:

Cov.:

AF XY:

0.0000541

AC XY:

AN XY:

73970

show subpopulations

Gnomad4 AFR

AF:

0.0000242

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000736

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000142

Hom.:

Bravo

AF:

0.0000302

ExAC

AF:

0.0000418

AC:

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

Dec 15, 2022

The c.646G>A (p.V216I) alteration is located in exon 6 (coding exon 6) of the RRAS gene. This alteration results from a G to A substitution at nucleotide position 646, causing the valine (V) at amino acid position 216 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Noonan syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 30, 2022

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. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The isoleucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. ClinVar contains an entry for this variant (Variation ID: 1366588). This variant has not been reported in the literature in individuals affected with RRAS-related conditions. This variant is present in population databases (rs748655822, gnomAD 0.01%). This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 216 of the RRAS protein (p.Val216Ile). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.083

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.43

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.31

Eigen

Benign

-0.65

Eigen_PC

Benign

-0.50

FATHMM_MKL

Benign

0.19

LIST_S2

Benign

0.59

M_CAP

Benign

0.015

MetaRNN

Benign

0.051

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.2

MutationTaster

Benign

0.98

PrimateAI

Benign

0.42

PROVEAN

Benign

-0.28

REVEL

Benign

0.078

Sift

Benign

0.24

Sift4G

Benign

0.33

Polyphen

0.0

Vest4

0.11

MutPred

0.35

Gain of sheet (P = 0.0477);

MVP

0.20

MPC

0.36

ClinPred

0.082

GERP RS

2.6

Varity_R

0.058

gMVP

0.29

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