Genetic Variant RRAS:p.Arg207Lys (chr19-49635613-C-T) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

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. 16/22 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

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: Genomics England PanelApp, ClinGen
cardiofaciocutaneous syndrome
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
Costello syndrome
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
Noonan syndrome with multiple lentigines
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
Noonan syndrome-like disorder with loose anagen hair
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

RRAS links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

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

BS2

High AC in GnomAdExome4 at 6 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006270.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RRAS	NM_006270.5	MANE Select	c.620G>A	p.Arg207Lys	missense	Exon 6 of 6	NP_006261.1	P10301

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RRAS	ENST00000246792.4	TSL:1 MANE Select	c.620G>A	p.Arg207Lys	missense	Exon 6 of 6	ENSP00000246792.2	P10301
RRAS	ENST00000962270.1		c.659G>A	p.Arg220Lys	missense	Exon 7 of 7	ENSP00000632329.1
RRAS	ENST00000928399.1		c.629G>A	p.Arg210Lys	missense	Exon 6 of 6	ENSP00000598458.1

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

African (AFR)

AF:

0.00

AC:

AN:

27530

American (AMR)

AF:

0.00

AC:

AN:

24928

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

17952

East Asian (EAS)

AF:

0.00

AC:

AN:

33630

South Asian (SAS)

AF:

0.00

AC:

AN:

58638

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47002

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4906

European-Non Finnish (NFE)

AF:

0.00000591

AC:

AN:

1015266

Other (OTH)

AF:

0.00

AC:

AN:

51702

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.417

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

Cov.:

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.46

CADD

Benign

(source)

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

PhyloP100

0.34

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

Mutation Taster

=93/7

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over