rs151014532

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_ModerateBP6_Very_StrongBS2

The NM_006270.5(RRAS):c.145T>C(p.Phe49Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0013 in 1,589,086 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar.

Frequency

Genomes: 𝑓 0.0011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0013 ( 3 hom. )

Consequence

RRAS
NM_006270.5 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 3.20

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 -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.122727215).

BP6

Variant 19-49639954-A-G is Benign according to our data. Variant chr19-49639954-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 527791.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-49639954-A-G is described in Lovd as [Likely_pathogenic]. Variant chr19-49639954-A-G is described in Lovd as [Likely_benign].

BS2

High Homozygotes in GnomAdExome at 3 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RRAS	NM_006270.5 linkuse as main transcript	c.145T>C	p.Phe49Leu	missense_variant	1/6	ENST00000246792.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RRAS	ENST00000246792.4 linkuse as main transcript	c.145T>C	p.Phe49Leu	missense_variant	1/6	1	NM_006270.5	P1
RRAS	ENST00000601532.1 linkuse as main transcript	n.169T>C		non_coding_transcript_exon_variant	1/4	5

Frequencies

GnomAD3 genomes

AF:

0.00107

AC:

163

AN:

151900

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000218

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00187

Gnomad FIN

AF:

0.000754

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00194

Gnomad OTH

AF:

0.000480

GnomAD3 exomes

AF:

0.000708

AC:

152

AN:

214778

Hom.:

AF XY:

0.000682

AC XY:

AN XY:

118796

show subpopulations

Gnomad AFR exome

AF:

0.0000839

Gnomad AMR exome

AF:

0.000183

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00108

Gnomad FIN exome

AF:

0.000229

Gnomad NFE exome

AF:

0.00112

Gnomad OTH exome

AF:

0.000187

GnomAD4 exome

AF:

0.00133

AC:

1906

AN:

1437066

Hom.:

Cov.:

AF XY:

0.00132

AC XY:

941

AN XY:

714666

show subpopulations

Gnomad4 AFR exome

AF:

0.000282

Gnomad4 AMR exome

AF:

0.000184

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00161

Gnomad4 FIN exome

AF:

0.000420

Gnomad4 NFE exome

AF:

0.00150

Gnomad4 OTH exome

AF:

0.00136

GnomAD4 genome

AF:

0.00107

AC:

163

AN:

152020

Hom.:

Cov.:

AF XY:

0.00109

AC XY:

AN XY:

74346

show subpopulations

Gnomad4 AFR

AF:

0.000217

Gnomad4 AMR

AF:

0.000262

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00187

Gnomad4 FIN

AF:

0.000754

Gnomad4 NFE

AF:

0.00194

Gnomad4 OTH

AF:

0.000475

Alfa

AF:

0.00137

Hom.:

Bravo

AF:

0.000903

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00117

AC:

ExAC

AF:

0.000671

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2023	RRAS: PP3, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 06, 2020	This variant is associated with the following publications: (PMID: 28875981) -

RRAS-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 05, 2019

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

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Jan 20, 2020

Variant summary: RRAS c.145T>C (p.Phe49Leu) results in a non-conservative amino acid change located in the Small GTP-binding protein domain (IPR005225) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00071 in 214778 control chromosomes, predominantly at a frequency of 0.0011 within the Non-Finnish European subpopulation in the gnomAD database (exomes only), including 1 homozygote. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 440 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 Non-Finnish European origin. c.145T>C has been reported in the literature in an individuals affected with Gastric Cancer without strong evidence for causality (Vogelaar_2017). This report however, does not provide unequivocal conclusions about association of the variant with Noonan Syndrome and Related Conditions. To our knowledge, no experimental evidence demonstrating an impact on protein function has 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. -

Noonan syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 28, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Benign

-0.094

BayesDel_noAF

Uncertain

0.090

Cadd

Uncertain

Dann

Uncertain

1.0

DEOGEN2

Pathogenic

0.80

Eigen

Uncertain

0.38

Eigen_PC

Uncertain

0.37

FATHMM_MKL

Benign

0.76

LIST_S2

Uncertain

0.93

M_CAP

Pathogenic

0.46

MetaRNN

Benign

0.12

MetaSVM

Uncertain

-0.031

MutationAssessor

Benign

1.6

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.88

PROVEAN

Uncertain

-3.1

REVEL

Pathogenic

0.76

Sift

Benign

0.39

Sift4G

Benign

0.40

Polyphen

1.0

Vest4

0.45

MutPred

0.83

Loss of catalytic residue at F49 (P = 0.1209);

MVP

0.97

MPC

0.98

ClinPred

0.15

GERP RS

4.6

Varity_R

0.56

gMVP

0.83

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