3-138372950-G-C

Position:

• chr3-138372950-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 12 ACMG points: 12P and 0B. PP3 PS4_Supporting PM2_Supporting PM1 PM5 PS2 PS3_Supporting

This summary comes from the ClinGen Evidence Repository: The c.67G>C (p.Gly23Arg) variant in MRAS is a missense variant predicted to cause substitution of glycine by arginine at amino acid 23. This variant is absent from gnomAD v4 (PM2_Supporting). The computational predictor REVEL gives a score of 0.906, which is above the threshold of 0.7, evidence that correlates with impact to MRAS function (PP3). A different missense variant, c.68G>T (p.Gly23Val) PMID:28289718, ClinVar ID:635781, in the same codon has been classified as likely pathogenic for RASopathy by the ClinGen RASopathy VCEP (PM5). This variant resides within the P-loop (amino acids 20 – 27) of MRAS that is defined as a critical functional domain by the ClinGen RASopathy VCEP (PM1). ERK and AKT activation assays in HEK 293T cells showed constitutively active forms of MRAS indicating that this variant impacts protein function (PMID:31108500) (PS3_Supporting). This variant has been reported in 1 proband with features of RASopathy (PS4_Supporting; PMID:31108500). This variant has been identified as a de novo occurrence with confirmed parental relationships in 1 individual with features of RASopathy (PS2; PMID:31108500). Given the Moderate strength of gene-disease relationship between MRAS and autosomal dominant RASopathy, ClinGen’s sequence variant interpretation working group does not recommend the classification of variants in this gene beyond likely pathogenic. Based on ACMG/AMP criteria, this variant has enough supporting evidence to be classified as pathogenic; however, the RASopathy VCEP has downgraded this classification to likely pathogenic based on ClinGen policy. In summary, this variant currently meets the criteria to be classified as likely pathogenic for autosomal dominant RASopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy VCEP: PS2, PM1, PM5, PS3_P, PS4, P, PM2_P, PP3. (RASopathy VCEP specifications version 1.1; 9/17/2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA354671566/MONDO:0021060/087

• Frequency: Genomes: not found (cov: 32)
• Consequence: MRAS NM_001085049.3 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:2
• Conservation: PhyloP100: 9.92

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 12 ACMG points.

• PS2: For more information check the summary or visit ClinGen Evidence Repository.
• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM5: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MRAS	NM_001085049.3	c.67G>C	p.Gly23Arg	missense_variant	2/6	ENST00000423968.7	NP_001078518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MRAS	ENST00000423968.7	c.67G>C	p.Gly23Arg	missense_variant	2/6	1	NM_001085049.3	ENSP00000389682	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: reviewed by expert panel

Submissions by phenotype

RASopathy Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues	May 15, 2018	- -
Likely pathogenic, reviewed by expert panel	curation	ClinGen RASopathy Variant Curation Expert Panel	Sep 17, 2024	The c.67G>C (p.Gly23Arg) variant in MRAS is a missense variant predicted to cause substitution of glycine by arginine at amino acid 23. This variant is absent from gnomAD v4 (PM2_Supporting). The computational predictor REVEL gives a score of 0.906, which is above the threshold of 0.7, evidence that correlates with impact to MRAS function (PP3). A different missense variant, c.68G>T (p.Gly23Val) PMID:28289718, ClinVar ID:635781, in the same codon has been classified as likely pathogenic for RASopathy by the ClinGen RASopathy VCEP (PM5). This variant resides within the P-loop (amino acids 20 – 27) of MRAS that is defined as a critical functional domain by the ClinGen RASopathy VCEP (PM1). ERK and AKT activation assays in HEK 293T cells showed constitutively active forms of MRAS indicating that this variant impacts protein function (PMID:31108500) (PS3_Supporting). This variant has been reported in 1 proband with features of RASopathy (PS4_Supporting; PMID:31108500). This variant has been identified as a de novo occurrence with confirmed parental relationships in 1 individual with features of RASopathy (PS2; PMID:31108500). Given the Moderate strength of gene-disease relationship between MRAS and autosomal dominant RASopathy, ClinGen’s sequence variant interpretation working group does not recommend the classification of variants in this gene beyond likely pathogenic. Based on ACMG/AMP criteria, this variant has enough supporting evidence to be classified as pathogenic; however, the RASopathy VCEP has downgraded this classification to likely pathogenic based on ClinGen policy. In summary, this variant currently meets the criteria to be classified as likely pathogenic for autosomal dominant RASopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy VCEP: PS2, PM1, PM5, PS3_P, PS4, P, PM2_P, PP3. (RASopathy VCEP specifications version 1.1; 9/17/2024) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.40
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.80	D;D;T;D
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.96
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	.;.;D;T
M_CAP	Pathogenic	0.37	D
MetaRNN	Pathogenic	0.96	D;D;D;D
MetaSVM	Uncertain	0.65	D
MutationAssessor	Uncertain	2.8	M;M;.;M
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-7.4	D;D;D;D
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D;D;.;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	D;D;.;D
Vest4		0.91
MutPred		0.89		Gain of solvent accessibility (P = 0.0306);Gain of solvent accessibility (P = 0.0306);Gain of solvent accessibility (P = 0.0306);Gain of solvent accessibility (P = 0.0306);
MVP		0.97
MPC		2.4
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.91
gMVP		0.88

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

LitVar

Other links and lift over

dbSNP: rs1560171992; hg19: chr3-138091792;