11-14281612-G-A

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 5P and 4B. PM1PP2PP3_ModerateBS2

The NM_012250.6(RRAS2):c.517C>T(p.Arg173Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000484 in 1,444,908 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. R173R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

RRAS2
NM_012250.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.33

Publications

2 publications found

Variant links:

Genes affected

RRAS2 (HGNC:17271): (RAS related 2) This gene encodes a member of the R-Ras subfamily of Ras-like small GTPases. The encoded protein associates with the plasma membrane and may function as a signal transducer. This protein may play an important role in activating signal transduction pathways that control cell proliferation. Mutations in this gene are associated with the growth of certain tumors. Pseudogenes of this gene are found on chromosomes 1 and 2. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Apr 2010]

RRAS2 Gene-Disease associations (from GenCC):

Noonan syndrome
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
noonan syndrome 12
Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, Genomics England PanelApp
ovarian cancer
Inheritance: Unknown Classification: NO_KNOWN Submitted by: Ambry Genetics

RRAS2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM1

In a chain Ras-related protein R-Ras2 (size 199) in uniprot entity RRAS2_HUMAN there are 9 pathogenic changes around while only 2 benign (82%) in NM_012250.6

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 6 curated pathogenic missense variants (we use a threshold of 10). The gene has 1 curated benign missense variants. Gene score misZ: 1.7783 (below the threshold of 3.09). Trascript score misZ: 0.74497 (below the threshold of 3.09). GenCC associations: The gene is linked to noonan syndrome 12, Noonan syndrome, ovarian cancer.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.905

BS2

High AC in GnomAdExome4 at 7 AD,Unknown gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RRAS2	NM_012250.6 link	c.517C>T	p.Arg173Trp	missense_variant	Exon 5 of 6	ENST00000256196.9	NP_036382.2	P62070-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RRAS2	ENST00000256196.9 link	c.517C>T	p.Arg173Trp	missense_variant	Exon 5 of 6	1	NM_012250.6	ENSP00000256196.4		P62070-1

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

151950

Hom.:

Cov.:

Gnomad AFR

AF:

0.00

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000424

AC:

AN:

235582

AF XY:

0.00000784

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000466

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000484

AC:

AN:

1444908

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

718350

show subpopulations

African (AFR)

AF:

0.0000307

AC:

AN:

32548

American (AMR)

AF:

0.00

AC:

AN:

40822

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25832

East Asian (EAS)

AF:

0.0000258

AC:

AN:

38704

South Asian (SAS)

AF:

0.00

AC:

AN:

82190

European-Finnish (FIN)

AF:

0.0000750

AC:

AN:

53308

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5738

European-Non Finnish (NFE)

AF:

9.04e-7

AC:

AN:

1105900

Other (OTH)

AF:

0.00

AC:

AN:

59866

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

152068

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74326

African (AFR)

AF:

0.00

AC:

AN:

41470

American (AMR)

AF:

0.00

AC:

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4804

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10564

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67986

Other (OTH)

AF:

0.00

AC:

AN:

2116

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Jan 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 173 of the RRAS2 protein (p.Arg173Trp). This variant is present in population databases (rs782726211, gnomAD 0.005%). This variant has not been reported in the literature in individuals affected with RRAS2-related conditions. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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

Pathogenic

0.94

BayesDel_addAF

Pathogenic

0.41

BayesDel_noAF

Pathogenic

0.35

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.89

.;.;.;D;.;.;.;.

Eigen

Pathogenic

0.84

Eigen_PC

Pathogenic

0.73

FATHMM_MKL

Uncertain

0.90

LIST_S2

Pathogenic

0.99

D;.;.;D;.;.;D;D

M_CAP

Uncertain

0.24

MetaRNN

Pathogenic

0.90

D;D;D;D;D;D;D;D

MetaSVM

Uncertain

0.64

MutationAssessor

Pathogenic

4.2

.;.;.;H;.;.;.;.

PhyloP100

2.3

PrimateAI

Pathogenic

0.90

PROVEAN

Pathogenic

-6.9

D;D;D;D;D;D;D;D

REVEL

Pathogenic

0.85

Sift

Pathogenic

0.0

D;D;D;D;D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D;D;D;D;D

Polyphen

1.0

.;.;.;D;.;.;.;.

Vest4

0.71

MutPred

0.72

.;.;.;Loss of disorder (P = 0.0051);.;.;.;.;

MVP

0.91

MPC

2.0

ClinPred

1.0

GERP RS

4.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.97

gMVP

0.62

Mutation Taster

=39/61

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

11-14281612-G-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over