Genetic Variant RRAS:p.Arg207Lys (chr19-49635613-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_006270.5(RRAS):c.620G>A(p.Arg207Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000468 in 1,281,554 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000047 ( 0 hom. )

Consequence

RRAS
NM_006270.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.345

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.068453014).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RRAS	NM_006270.5 link	c.620G>A	p.Arg207Lys	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.620G>A	p.Arg207Lys	missense_variant	Exon 6 of 6	1	NM_006270.5	ENSP00000246792.2		P10301
RRAS	ENST00000601532.1 link	n.*199G>A		downstream_gene_variant		5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000468

AC:

AN:

1281554

Hom.:

Cov.:

AF XY:

0.00000160

AC XY:

AN XY:

625526

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000591

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 05, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R207K variant (also known as c.620G>A), located in coding exon 6 of the RRAS gene, results from a G to A substitution at nucleotide position 620. The arginine at codon 207 is replaced by lysine, an amino acid with highly similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.46

CADD

Benign

DANN

Benign

0.93

DEOGEN2

Benign

0.24

Eigen

Benign

-0.76

Eigen_PC

Benign

-0.50

FATHMM_MKL

Benign

0.62

LIST_S2

Benign

0.50

M_CAP

Benign

0.014

MetaRNN

Benign

0.068

MetaSVM

Benign

-0.99

MutationAssessor

Benign

-0.80

PrimateAI

Uncertain

0.67

PROVEAN

Benign

0.52

REVEL

Benign

0.075

Sift

Benign

0.83

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.097

MutPred

0.30

Gain of methylation at R207 (P = 0.0121);

MVP

0.85

MPC

0.45

ClinPred

0.25

GERP RS

4.0

Varity_R

0.070

gMVP

0.38

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over