19-49636675-C-T

Variant names:

Variant summary

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

The NM_006270.5(RRAS):c.397G>A(p.Asp133Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00594 in 1,614,112 control chromosomes in the GnomAD database, including 33 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0038 ( 1 hom., cov: 31)

Exomes 𝑓: 0.0062 ( 32 hom. )

Consequence

RRAS
NM_006270.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 7.27

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 Benign. Variant got -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.014026105).

BP6

Variant 19-49636675-C-T is Benign according to our data. Variant chr19-49636675-C-T is described in ClinVar as [Benign]. Clinvar id is 457987.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-49636675-C-T is described in Lovd as [Benign].

BS2

High Homozygotes in GnomAdExome4 at 32 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RRAS	NM_006270.5 link	c.397G>A	p.Asp133Asn	missense_variant	Exon 4 of 6	ENST00000246792.4	NP_006261.1	P10301A0A024QZF2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RRAS	ENST00000246792.4 link	c.397G>A	p.Asp133Asn	missense_variant	Exon 4 of 6	1	NM_006270.5	ENSP00000246792.2		P10301
RRAS	ENST00000601532.1 link	n.537G>A		non_coding_transcript_exon_variant	Exon 3 of 4	5

Frequencies

GnomAD3 genomes

AF:

0.00381

AC:

580

AN:

152176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000820

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000851

Gnomad ASJ

AF:

0.00375

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00226

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00716

Gnomad OTH

AF:

0.00335

GnomAD3 exomes

AF:

0.00431

AC:

1082

AN:

251222

Hom.:

AF XY:

0.00449

AC XY:

610

AN XY:

135818

show subpopulations

Gnomad AFR exome

AF:

0.000493

Gnomad AMR exome

AF:

0.000578

Gnomad ASJ exome

AF:

0.00228

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000425

Gnomad FIN exome

AF:

0.00425

Gnomad NFE exome

AF:

0.00798

Gnomad OTH exome

AF:

0.00326

GnomAD4 exome

AF:

0.00616

AC:

9003

AN:

1461818

Hom.:

Cov.:

AF XY:

0.00598

AC XY:

4352

AN XY:

727208

show subpopulations

Gnomad4 AFR exome

AF:

0.000657

Gnomad4 AMR exome

AF:

0.000671

Gnomad4 ASJ exome

AF:

0.00298

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000568

Gnomad4 FIN exome

AF:

0.00474

Gnomad4 NFE exome

AF:

0.00746

Gnomad4 OTH exome

AF:

0.00442

GnomAD4 genome

AF:

0.00381

AC:

580

AN:

152294

Hom.:

Cov.:

AF XY:

0.00360

AC XY:

268

AN XY:

74478

show subpopulations

Gnomad4 AFR

AF:

0.000818

Gnomad4 AMR

AF:

0.000850

Gnomad4 ASJ

AF:

0.00375

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00226

Gnomad4 NFE

AF:

0.00716

Gnomad4 OTH

AF:

0.00331

Alfa

AF:

0.00539

Hom.:

Bravo

AF:

0.00342

TwinsUK

AF:

0.00809

AC:

ALSPAC

AF:

0.00752

AC:

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00640

AC:

ExAC

AF:

0.00498

AC:

605

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00698

EpiControl

AF:

0.00676

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

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

RRAS: BS2 -

Apr 11, 2017

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The RRAS c.397G>A (p.Asp133Asn) variant involves the alteration of a conserved nucleotide, resulting in missense change. 2/4 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 605/121088 control chromosomes (including one homozygote) from ExAC at a frequency of 0.0049964, which is approximately 1999 times the estimated maximal expected allele frequency of a pathogenic RRAS variant (0.0000025), suggesting this variant is likely a benign polymorphism. Taken together, this variant is classified as Benign. -

Jun 01, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

RRAS-related disorder

Benign:1

May 30, 2019

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). -

not specified

Benign:1

Dec 28, 2018

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Asp133Asn in exon 4 of RRAS: This variant is not expected to have clinical significance because it has been identified in 0.84% (558/66576) of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs61760904). -

Noonan syndrome

Benign:1

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.31

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.36

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.77

Eigen

Benign

0.12

Eigen_PC

Benign

0.016

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.94

M_CAP

Uncertain

0.16

MetaRNN

Benign

0.014

MetaSVM

Benign

-0.35

MutationAssessor

Benign

1.0

PrimateAI

Uncertain

0.76

PROVEAN

Uncertain

-3.9

REVEL

Uncertain

0.41

Sift

Benign

0.060

Sift4G

Uncertain

0.038

Polyphen

0.98

Vest4

0.51

MVP

0.81

MPC

0.67

ClinPred

0.036

GERP RS

3.1

Varity_R

0.66

gMVP

0.51

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