3-138372905-A-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_001085049.3(MRAS):c.22A>G(p.Ser8Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000229 in 1,546,898 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S8T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00017 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00024 ( 1 hom. )

Consequence

MRAS
NM_001085049.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: 6.23

Variant links:

Genes affected

MRAS (HGNC:7227): (muscle RAS oncogene homolog) This gene encodes a member of the Ras family of small GTPases. These membrane-associated proteins function as signal transducers in multiple processes including cell growth and differentiation, and dysregulation of Ras signaling has been associated with many types of cancer. The encoded protein may play a role in the tumor necrosis factor-alpha and MAP kinase signaling pathways. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Nov 2011]

MRAS links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008371383).

BP6

Variant 3-138372905-A-G is Benign according to our data. Variant chr3-138372905-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 496408.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=1, Uncertain_significance=1}.

BS2

High AC in GnomAd at 27 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MRAS	NM_001085049.3 linkuse as main transcript	c.22A>G	p.Ser8Gly	missense_variant	2/6	ENST00000423968.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MRAS	ENST00000423968.7 linkuse as main transcript	c.22A>G	p.Ser8Gly	missense_variant	2/6	1	NM_001085049.3	P1	O14807-1

Frequencies

GnomAD3 genomes

AF:

0.000177

AC:

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00498

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000539

AC:

104

AN:

192782

Hom.:

AF XY:

0.000670

AC XY:

AN XY:

105960

show subpopulations

Gnomad AFR exome

AF:

0.0000858

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00457

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000235

GnomAD4 exome

AF:

0.000235

AC:

328

AN:

1394592

Hom.:

Cov.:

AF XY:

0.000316

AC XY:

219

AN XY:

692462

show subpopulations

Gnomad4 AFR exome

AF:

0.0000349

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000595

Gnomad4 SAS exome

AF:

0.00395

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000101

Gnomad4 OTH exome

AF:

0.000209

GnomAD4 genome

AF:

0.000171

AC:

AN:

152306

Hom.:

Cov.:

AF XY:

0.000215

AC XY:

AN XY:

74482

show subpopulations

Gnomad4 AFR

AF:

0.0000481

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00477

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000618

Hom.:

Bravo

AF:

0.0000416

ExAC

AF:

0.000725

AC:

Asia WGS

AF:

0.00173

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 05, 2017	Variant summary: The MRAS c.22A>G (p.Ser8Gly) variant involves the alteration of a conserved nucleotide. 2/3 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 88/120948 control chromosomes from ExAC, predominantly observed in the South Asian subpopulation at a frequency of 0.005263 (86/16342). This frequency is about 2105 times the estimated maximal expected allele frequency of a pathogenic MRAS variant (0.0000025), suggesting this is likely a benign polymorphism found primarily in the populations of South Asian origin. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories. Taken together, this variant is classified as likely benign. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Oct 28, 2023	- -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 23, 2021

The p.S8G variant (also known as c.22A>G), located in coding exon 1 of the MRAS gene, results from an A to G substitution at nucleotide position 22. The serine at codon 8 is replaced by glycine, an amino acid with 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

0.097

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.32

Cadd

Benign

Dann

Benign

0.96

DEOGEN2

Benign

0.17

T;T;T;T

Eigen

Benign

-0.11

Eigen_PC

Benign

0.13

FATHMM_MKL

Pathogenic

0.97

M_CAP

Benign

0.020

MetaRNN

Benign

0.0084

T;T;T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

1.2

L;L;.;L

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Uncertain

0.78

PROVEAN

Benign

-1.2

N;N;D;N

REVEL

Benign

0.068

Sift

Benign

0.17

T;T;.;T

Sift4G

Benign

0.47

T;T;T;T

Polyphen

0.0

B;B;.;B

Vest4

0.21

MutPred

0.24

Loss of glycosylation at T3 (P = 0.0104);Loss of glycosylation at T3 (P = 0.0104);Loss of glycosylation at T3 (P = 0.0104);Loss of glycosylation at T3 (P = 0.0104);

MVP

0.67

MPC

0.97

ClinPred

0.049

GERP RS

5.6

Varity_R

0.14

gMVP

0.74

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over