NM_006270.5:c.64G>A

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_006270.5(RRAS):c.64G>A(p.Gly22Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign 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. G22W) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.2e-7 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

RRAS
NM_006270.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.756

Publications

1 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.1106703).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RRAS	NM_006270.5 link	c.64G>A	p.Gly22Arg	missense_variant	Exon 1 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.64G>A	p.Gly22Arg	missense_variant	Exon 1 of 6	1	NM_006270.5	ENSP00000246792.2		P10301
RRAS	ENST00000601532.1 link	n.88G>A		non_coding_transcript_exon_variant	Exon 1 of 4	5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

7.23e-7

AC:

AN:

1383796

Hom.:

Cov.:

AF XY:

0.00000146

AC XY:

AN XY:

685532

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

29382

American (AMR)

AF:

0.00

AC:

AN:

35786

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24394

East Asian (EAS)

AF:

0.00

AC:

AN:

33810

South Asian (SAS)

AF:

0.00

AC:

AN:

80322

European-Finnish (FIN)

AF:

0.00

AC:

AN:

36912

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4286

European-Non Finnish (NFE)

AF:

9.25e-7

AC:

AN:

1081586

Other (OTH)

AF:

0.00

AC:

AN:

57318

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Noonan syndrome

Uncertain:1

Apr 30, 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 22 of the RRAS protein (p.Gly22Arg). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with RRAS-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". 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

0.26

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.47

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.30

Eigen

Benign

-0.56

Eigen_PC

Benign

-0.36

FATHMM_MKL

Benign

0.10

LIST_S2

Benign

0.55

M_CAP

Uncertain

0.16

MetaRNN

Benign

0.11

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.34

PhyloP100

0.76

PrimateAI

Pathogenic

0.90

PROVEAN

Benign

-0.21

REVEL

Benign

0.054

Sift

Benign

0.95

Sift4G

Benign

0.35

Polyphen

0.0

Vest4

0.16

MutPred

0.26

Loss of relative solvent accessibility (P = 0.0404);

MVP

0.80

MPC

0.53

ClinPred

0.58

GERP RS

2.4

PromoterAI

0.010

Neutral

(source)

Varity_R

0.042

gMVP

0.56

Mutation Taster

=88/12

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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NM_006270.5:c.64G>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