11-14281690-G-A

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 4P and 4B. PM1PP2PP3BS2

The NM_012250.6(RRAS2):c.439C>T(p.Arg147Trp) variant causes a missense change. The variant allele was found at a frequency of 0.0000219 in 1,597,164 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R147Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000022 ( 0 hom. )

Consequence

RRAS2
NM_012250.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter P:1U:2

Conservation

PhyloP100: 3.95

Publications

1 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 0 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, 0.84

BS2

High AC in GnomAdExome4 at 32 AD,Unknown gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RRAS2	NM_012250.6 link	c.439C>T	p.Arg147Trp	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.439C>T	p.Arg147Trp	missense_variant	Exon 5 of 6	1	NM_012250.6	ENSP00000256196.4		P62070-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152142

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.0000147

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.0000170

AC:

AN:

234658

AF XY:

0.00000787

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000586

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000183

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000221

AC:

AN:

1445022

Hom.:

Cov.:

AF XY:

0.0000251

AC XY:

AN XY:

718364

show subpopulations

African (AFR)

AF:

0.0000616

AC:

AN:

32468

American (AMR)

AF:

0.00

AC:

AN:

40282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25804

East Asian (EAS)

AF:

0.0000257

AC:

AN:

38974

South Asian (SAS)

AF:

0.0000488

AC:

AN:

82012

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53282

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5744

European-Non Finnish (NFE)

AF:

0.0000226

AC:

AN:

1106582

Other (OTH)

AF:

0.00

AC:

AN:

59874

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152142

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74324

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41434

American (AMR)

AF:

0.00

AC:

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10590

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68028

Other (OTH)

AF:

0.000478

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.442

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000564

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Noonan syndrome 12

Pathogenic:1

Molecular Biology Laboratory, Department of Zoology, Quaid-i-azam University

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:research

- -

RRAS2-related disorder

Uncertain:1

Dec 15, 2023

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The RRAS2 c.439C>T variant is predicted to result in the amino acid substitution p.Arg147Trp. This variant has been reported in the homozygous state in an individual from a cohort of mucopolysaccharidoses patients; however, a second potentially causative variant was also reported in the patient (Family L, Gul et al. 2023. PubMed ID: 37091798). This variant is reported in 0.0054% of alleles in individuals of East Asian descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

not provided

Uncertain:1

Dec 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

RRAS2: PP3 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.49

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Pathogenic

0.25

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.88

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

Eigen

Uncertain

0.32

Eigen_PC

Uncertain

0.22

FATHMM_MKL

Uncertain

0.97

LIST_S2

Pathogenic

0.98

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

M_CAP

Uncertain

0.25

MetaRNN

Pathogenic

0.84

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

MetaSVM

Uncertain

0.34

MutationAssessor

Uncertain

2.6

.;.;.;M;.;.;.;.

PhyloP100

3.9

PrimateAI

Pathogenic

0.85

PROVEAN

Pathogenic

-5.5

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

REVEL

Pathogenic

0.69

Sift

Uncertain

0.0050

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

Sift4G

Pathogenic

0.0010

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

Polyphen

1.0

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

Vest4

0.80

MutPred

0.45

.;.;.;Gain of catalytic residue at L145 (P = 0.0065);.;.;.;.;

MVP

0.89

MPC

1.9

ClinPred

0.93

GERP RS

3.1

Varity_R

0.71

gMVP

0.55

Mutation Taster

=45/55

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

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.

11-14281690-G-A

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