NM_001085049.3:c.68G>T

Variant names:

• chr3-138372951-G-T
• rs1576359216
• NM_001085049.3:c.68G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 11 ACMG points: 11P and 0B. PM1 PS2 PP3 PS3_Moderate PS4_Supporting PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The c.68G>T (p.Gly23Val) variant in MRAS is a missense variant predicted to cause substitution of glycine by valine at amino acid 23. This variant has a minor allele frequency of 0.00008624% (1/1159522) in the European (non-Finnish) population in gnomAD v4 (PM2_Supporting). The computational predictor REVEL gives a score of 0.923, which is above the threshold of 0.7, evidence that correlates with impact to MRAS function (PP3). 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). This variant has been identified in 1 individual with features of RASopathy (PS4_Supporting; PMID:28289718). This variant has been identified as a de novo occurrence with confirmed parental relationships in 1 individual with features of RASopathy (PS2; PMID:28289718). RAS and ERK activation assays in HEK293T/17 showed constitutively active forms of MRAS indicating that this variant impacts protein function (PMID:28289718) (PS3_Moderate). 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 alone, 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, PS3_M, PM1, PS4_P, PM2_P, PP3. (RASopathy VCEP specifications version 1.1; 9/17/2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA354671596/MONDO:0021060/087

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: MRAS NM_001085049.3 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:8
• Conservation: PhyloP100: 9.92
• Publications: 6 publications found

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 Gene-Disease associations (from GenCC):

• Noonan syndrome 11

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• Noonan syndrome

  Inheritance: AD Classification: MODERATE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• 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

ACMG classification

Our verdict: Likely_pathogenic. The variant received 11 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.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001085049.3. 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
	MRAS	NM_001085049.3	MANE Select	c.68G>T	p.Gly23Val	missense	Exon 2 of 6	NP_001078518.1	O14807-1
	MRAS	NM_001252090.2		c.68G>T	p.Gly23Val	missense	Exon 2 of 6	NP_001239019.1	O14807-1
	MRAS	NM_012219.4		c.68G>T	p.Gly23Val	missense	Exon 2 of 6	NP_036351.3	O14807-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MRAS	ENST00000423968.7	TSL:1 MANE Select	c.68G>T	p.Gly23Val	missense	Exon 2 of 6	ENSP00000389682.2	O14807-1
	MRAS	ENST00000949757.1		c.68G>T	p.Gly23Val	missense	Exon 3 of 7	ENSP00000619816.1
	MRAS	ENST00000949759.1		c.68G>T	p.Gly23Val	missense	Exon 2 of 6	ENSP00000619818.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.08e-7 AC: 1 AN: 1412440 Hom.: 0 Cov.: 33 AF XY: 0.00000143 AC XY: 1 AN XY: 701546

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 29932

American (AMR) AF: 0.00 AC: 0 AN: 35818

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25216

East Asian (EAS) AF: 0.00 AC: 0 AN: 34312

South Asian (SAS) AF: 0.00 AC: 0 AN: 79064

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53030

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5212

European-Non Finnish (NFE) AF: 9.16e-7 AC: 1 AN: 1091506

Other (OTH) AF: 0.00 AC: 0 AN: 58350

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
5	-	-	Noonan syndrome 11 (5)
2	-	-	RASopathy (2)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.43
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.89	D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.86	D
M_CAP	Pathogenic	0.37	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	0.88	D
MutationAssessor	Pathogenic	3.6	H
PhyloP100		9.9
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-8.2	D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.91
MutPred		0.92		Loss of ubiquitination at K26 (P = 0.0615)
MVP		0.95
MPC		2.5
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.97
gMVP		0.94
Mutation Taster		=2/98	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1576359216; hg19: chr3-138091793;