Genetic Variant RRAS:p.Cys215Trp (chr19-49635588-G-C) – ACMG Classification: Uncertain_significance (5 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1PM2PP3

The NM_006270.5(RRAS):c.645C>G(p.Cys215Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,444,220 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C215R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)

Exomes 𝑓: 7.7e-7 ( 0 hom. )

Consequence

RRAS
NM_006270.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0220

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, PanelApp Australia, 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: Uncertain_significance. The variant received 5 ACMG points.

PM1

In a lipid_moiety_binding_region S-geranylgeranyl cysteine (size 0) in uniprot entity RRAS_HUMAN

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.773

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.645C>G	p.Cys215Trp	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.645C>G	p.Cys215Trp	missense	Exon 6 of 6	ENSP00000246792.2	P10301
RRAS	ENST00000962270.1		c.684C>G	p.Cys228Trp	missense	Exon 7 of 7	ENSP00000632329.1
RRAS	ENST00000928399.1		c.654C>G	p.Cys218Trp	missense	Exon 6 of 6	ENSP00000598458.1

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152038

Hom.:

Cov.:

show subpopulations

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

7.74e-7

AC:

AN:

1292182

Hom.:

Cov.:

AF XY:

0.00000159

AC XY:

AN XY:

630146

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

28092

American (AMR)

AF:

0.00

AC:

AN:

25012

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18076

East Asian (EAS)

AF:

0.00

AC:

AN:

34772

South Asian (SAS)

AF:

0.00

AC:

AN:

59078

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47652

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4898

European-Non Finnish (NFE)

AF:

9.78e-7

AC:

AN:

1022184

Other (OTH)

AF:

0.00

AC:

AN:

52418

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

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

AF:

0.00000658

AC:

AN:

152038

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74254

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41386

American (AMR)

AF:

0.00

AC:

AN:

15262

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4808

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68002

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.625

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.81

BayesDel_addAF

Pathogenic

0.20

BayesDel_noAF

Uncertain

0.040

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.80

Eigen

Benign

0.020

Eigen_PC

Benign

-0.18

FATHMM_MKL

Benign

0.35

LIST_S2

Benign

0.74

M_CAP

Uncertain

0.27

MetaRNN

Pathogenic

0.77

MetaSVM

Benign

-0.35

MutationAssessor

Pathogenic

3.0

PhyloP100

-0.022

PrimateAI

Uncertain

0.66

PROVEAN

Pathogenic

-5.3

REVEL

Uncertain

0.57

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.58

MutPred

0.62

Gain of MoRF binding (P = 6e-04)

MVP

0.79

MPC

1.5

ClinPred

0.97

GERP RS

-2.8

Varity_R

0.88

gMVP

0.72

Mutation Taster

=52/48

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

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

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over