19-49635602-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_006270.5(RRAS):c.631G>A(p.Gly211Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000772 in 1,438,128 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000099 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000075 ( 1 hom. )

Consequence

RRAS
NM_006270.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: -0.548

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

Noonan syndrome and Noonan-related syndrome
Inheritance: AD Classification: STRONG Submitted by: G2P
Noonan syndrome
Inheritance: AD Classification: MODERATE, LIMITED Submitted by: ClinGen, Genomics England PanelApp

RRAS links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.05129853).

BS2

High AC in GnomAd4 at 15 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RRAS	NM_006270.5 link	c.631G>A	p.Gly211Arg	missense_variant	Exon 6 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.631G>A	p.Gly211Arg	missense_variant	Exon 6 of 6	1	NM_006270.5	ENSP00000246792.2		P10301
RRAS	ENST00000601532.1 link	n.*210G>A		downstream_gene_variant		5

Frequencies

GnomAD3 genomes

AF:

0.0000990

AC:

AN:

151538

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000146

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000389

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000588

AC:

AN:

152940

AF XY:

0.0000370

show subpopulations

Gnomad AFR exome

AF:

0.000312

Gnomad AMR exome

AF:

0.0000611

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000890

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000386

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000746

AC:

AN:

1286590

Hom.:

Cov.:

AF XY:

0.0000812

AC XY:

AN XY:

627864

show subpopulations

African (AFR)

AF:

0.000325

AC:

AN:

27732

American (AMR)

AF:

0.0000401

AC:

AN:

24922

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18034

East Asian (EAS)

AF:

0.00

AC:

AN:

33962

South Asian (SAS)

AF:

0.000101

AC:

AN:

59164

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47288

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4912

European-Non Finnish (NFE)

AF:

0.0000727

AC:

AN:

1018502

Other (OTH)

AF:

0.000115

AC:

AN:

52074

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000990

AC:

AN:

151538

Hom.:

Cov.:

AF XY:

0.000135

AC XY:

AN XY:

73946

show subpopulations

African (AFR)

AF:

0.000146

AC:

AN:

41208

American (AMR)

AF:

0.00

AC:

AN:

15202

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.000389

AC:

AN:

5142

South Asian (SAS)

AF:

0.00

AC:

AN:

4790

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10530

Middle Eastern (MID)

AF:

0.00

AC:

AN:

308

European-Non Finnish (NFE)

AF:

0.000103

AC:

AN:

67912

Other (OTH)

AF:

0.00

AC:

AN:

2072

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000132

Hom.:

Bravo

AF:

0.000117

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000582

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:2

Aug 06, 2022

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

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 10, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.631G>A (p.G211R) 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 631, causing the glycine (G) at amino acid position 211 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Noonan syndrome

Uncertain:1

Dec 25, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 211 of the RRAS protein (p.Gly211Arg). This variant is present in population databases (rs369588682, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with RRAS-related conditions. ClinVar contains an entry for this variant (Variation ID: 582576). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The arginine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.44

CADD

Benign

7.7

(source)

DANN

Benign

0.83

DEOGEN2

Benign

0.28

Eigen

Benign

-0.89

Eigen_PC

Benign

-0.84

FATHMM_MKL

Benign

0.035

LIST_S2

Benign

0.35

M_CAP

Benign

0.022

MetaRNN

Benign

0.051

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.11

PhyloP100

-0.55

PrimateAI

Benign

0.44

PROVEAN

Benign

0.34

REVEL

Benign

0.054

Sift

Benign

0.17

Sift4G

Benign

0.18

Polyphen

0.0090

Vest4

0.14

MutPred

0.30

Gain of MoRF binding (P = 2e-04);

MVP

0.61

MPC

0.53

ClinPred

0.036

GERP RS

1.8

Varity_R

0.094

gMVP

0.38

Mutation Taster

=96/4

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over