MRAS

protein-coding

muscle RAS oncogene homolog, the group of RAS type GTPase family

Gene summary

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]

MANE transcript

NM_001085049.3

Inheritance

ClinVar variants

P:5U:121B:84

Top phenotype

Noonan syndrome 11

gnomAD constraint

pLI —, LoF o/e 0

Max pathogenic AF

—

Genomic locus

chr3:138,347,648-138,405,534

External References & Databases

Ensembl (ENSG00000158186)

Transcript & Mutation Effects

hg38 • Region Span ~57.9 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Noonan syndrome 11DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0032786

Submitter: G2P

Noonan syndromeMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0018997

Submitter: ClinGen

MRAS was reported in relation to autosomal dominant Noonan syndrome as early as 2017 (Higgins et al., PMID: 28289718). At least 4 unique missense variants have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Four variants in this gene have been reported in at least 6 probands in 4 publications (PMIDs: 28289718, 31173466, 31108500, 34080768). This gene-disease association is supported by the interaction of MRAS with the Ras/MAPK pathway, which is associated with the Noonan Syndrome phenotype (PMID: 23875798), as well as interaction with SHOC2 and PPP1CB in the SHOC2-MRAS-PP1C holophosphatase complex (PMID: 35831509). The ClinGen RASopathy Expert Panel has assessed MRAS for associations with Noonan syndrome-like disorder with loose anagen hair, Noonan syndrome with multiple lentigines, Costello syndrome, and cardiofaciocutaneous syndrome, however no evidence was reported. In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This curation was approved by the ClinGen RASopathy Expert Panel on 8/27/20. This gene-disease pair was originally evaluated by the ClinGen RASopathy Expert Panel on 8/27/20. It was reevaluated on 12/14/22. As a result of this reevaluation, the classification did not change (SOP Version 9).

Noonan syndrome 11MODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0032786

Submitter: Ambry Genetics

Noonan syndrome 11STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0032786

Submitter: PanelApp Australia

Noonan syndrome 11STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0032786

Submitter: Labcorp Genetics (formerly Invitae)

Noonan syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0018997

Submitter: Orphanet

Noonan syndrome 11STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0032786

Submitter: Genomics England PanelApp

Clinical Genomic Database (CGD)

Noonan syndrome 11AD

Manifestation: Cardiovascular; Craniofacial; Musculoskeletal; Neurologic

Intervention: Cardiovascular

Rationale: Individuals have been described with cardiac disease, inclduing cardiomyopathy as well as structural cardiac anomalies, and awareness may allow early diagnosis and management (surgical management has been described)

Refs: 28289718; 31173466

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to MRAS variants in ClinVar

7 Conditions Cataloged

not providedTotal: 212

Inborn genetic diseasesTotal: 99

not specifiedTotal: 25

Noonan syndrome 11Total: 10

MRAS-related disorderTotal: 8

RASopathyTotal: 7

Male infertility with azoospermia or oligozoospermia due to single gene mutationTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001085049.3. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous				80 clinvar	2 clinvar	82
missense		5 clinvar	111 clinvar	2 clinvar		118
nonsense			3 clinvar			3
start loss						0
frameshift			5 clinvar			5
splice donor/acceptor (+/-2bp)			2 clinvar			2
Total	0	5	121	82	2	210

Highest pathogenic variant AF is 0.0000024784467

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 59 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001085049.3	RefSeq	NP_001078518.1	5	MANE Select
ENST00000423968.7	Ensembl	ENSP00000389682.2	5	MANE Select
NM_001252090.2	RefSeq	NP_001239019.1	5	Standard
NM_001252091.1	RefSeq	NP_001239020.1	4	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Autophagy - animal - Homo sapiens (human)
HTLV-I infection - Homo sapiens (human)
Regulation of actin cytoskeleton - Homo sapiens (human)
Mitophagy - animal - Homo sapiens (human)
Apelin signaling pathway - Homo sapiens (human)

Biological Process

Ras protein signal transduction
multicellular organism development
muscle organ development
actin cytoskeleton organization
cellular response to leukemia inhibitory factor

Molecular Function

GTPase activity
protein binding
GTP binding
GTP-dependent protein binding

Cellular Component

plasma membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000289104
Coding exons: 5
Length: 57837
Individuals with no LoFs: 125714
Homozygous LoFs: 0
Heterozygous LoFs: 8
Defined: 125722
p: 0.0000318

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.33	56	131	0.428	0.00000816	1393
Missense (PolyPhen)		12	56.376	0.21286		612
Synonymous	0.594	46	51.4	0.895	0.00000347	375
Loss of Function	2.64	0	8.14	0.00	3.42e-7	109

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00025	0.00025	rare
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.000028	0.000026	rare
South Asian	0	0.0	absent
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: May serve as an important signal transducer for a novel upstream stimuli in controlling cell proliferation. Weakly activates the MAP kinase pathway. {ECO:0000269|PubMed:16630891}.;

Recessive Scores

pRec: 0.178

Intolerance Scores

RVIS EVS: -0.14
RVIS percentile EVS: 42.88

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.902

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium