GeneBe

RASA1

protein-coding

RAS p21 protein activator 1, the group of Pleckstrin homology domain containing|SH2 domain containing|C2 and RasGAP domain containing

Gene summary

The protein encoded by this gene is located in the cytoplasm and is part of the GAP1 family of GTPase-activating proteins. The gene product stimulates the GTPase activity of normal RAS p21 but not its oncogenic counterpart. Acting as a suppressor of RAS function, the protein enhances the weak intrinsic GTPase activity of RAS proteins resulting in the inactive GDP-bound form of RAS, thereby allowing control of cellular proliferation and differentiation. Mutations leading to changes in the binding sites of either protein are associated with basal cell carcinomas. Mutations also have been associated with hereditary capillary malformations (CM) with or without arteriovenous malformations (AVM) and Parkes Weber syndrome. Alternative splicing results in two isoforms where the shorter isoform, lacking the N-terminal hydrophobic region but retaining the same activity, appears to be abundantly expressed in placental but not adult tissues. [provided by RefSeq, May 2012]

Previous symbols:
  • RASA

MANE transcript

NM_002890.3

Inheritance

AD

ClinVar variants

P:310U:648B:437

Top phenotype

Capillary malformation-arteriovenous malformation 1; Parkes Weber syndrome; Spinal arteriovenous anomalies

gnomAD constraint

pLI —, LoF o/e 0.05

Max pathogenic AF

—

Genomic locus

chr5:87,267,883-87,391,931

External References & Databases

Ensembl (ENSG00000145715)NCBI Gene (5921)OMIM (139150)HGNC:9871GenCCUniProt (P20936)AlphaFoldClinVar (RASA1)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~124.0 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

telangiectasia, hereditary hemorrhagic, type 1NO_KNOWN

Inheritance Pattern: AD

Disease ID:MONDO:0008535

Submitter: Labcorp Genetics (formerly Invitae)

capillary malformation-arteriovenous malformation 1LIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0020783

Submitter: G2P

Parkes Weber syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0012017

Submitter: Orphanet

Noonan syndromeNO_KNOWN

Inheritance Pattern: AD

Disease ID:MONDO:0018997

Submitter: ClinGen

There have been multiple reported cases in the literature showing that RASA1 variants can cause cardiovascular anomalies such as capillary malformation-arteriovenous malformation syndrome (CM-AVM)(Ilari, Agosta, & Bacino, 2016; Macmurdo et al., 2016). These studies suggest that these patients may possess clinical features of Noonan syndrome (NS). However, patients with additional phenotypes such as hypotonia and severe ID all possess secondary causes of disease apart from RASA1 variation. Therefore, there is no convincing genetic evidence that supports the association of RASA1 and NS. In fact, RASA1 should most likely only be associated with cardiovascular anomalies. RASA1’s association with NS is Disputed. The ClinGen RASopathy Expert Panel found no evidence associating RASA1 with cardiofaciocutaneous syndrome, Costello syndrome, NS with loose anagen hair, or NS with multiple lentigines. This curation was approved by the ClinGen RASopathy Gene Curation Expert Panel on 6/7/18 (SOP Version 5).

capillary malformation-arteriovenous malformation 1STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0020783

Submitter: Genomics England PanelApp

capillary malformation-arteriovenous malformation 1STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0020783

Submitter: PanelApp Australia

capillary malformation-arteriovenous malformation 1STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0020783

Submitter: Labcorp Genetics (formerly Invitae)

capillary malformation-arteriovenous malformation 1DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0020783

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Capillary malformation-arteriovenous malformation 1; Parkes Weber syndrome; Spinal arteriovenous anomaliesAD

Manifestation: Cardiovascular; Musculoskeletal

Intervention: Cardiovascular

Rationale: Life-threatening complications of arteriovenous malformations and arteriovenous fistulas can include bleeding, congestive heart failure, and/or neurologic consequences, and surveillance may allow early detection and medical/surgical management, which may decrease morbidity/mortality

Refs: 14639529; 15917201; 18363760; 18446851; 20007727; 21348050; 20821215; 22342634; 24038909Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to RASA1 variants in ClinVar

23 Conditions Cataloged
Capillary malformation-arteriovenous malformation syndromeTotal: 1336
Cardiovascular phenotypeTotal: 493
not providedTotal: 229
Capillary malformation-arteriovenous malformation 1Total: 140
RASA1-related disorderTotal: 91
not specifiedTotal: 68
Basal cell carcinoma, susceptibility to, 1Total: 19
Vascular malformationTotal: 4

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_002890.3. 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.

EffectPLPVUSLBBSum
synonymous
1
clinvar
12
clinvar
361
clinvar
 374
missense
4
clinvar
3
clinvar
622
clinvar
74
clinvar
2
clinvar
 705
nonsense
56
clinvar
10
clinvar
2
clinvar
 68
start loss
1
clinvar
 1
frameshift
125
clinvar
37
clinvar
1
clinvar
 163
splice donor/acceptor (+/-2bp)
22
clinvar
52
clinvar
10
clinvar
 84
Total20710364843521395

Highest pathogenic variant AF is 0.0000065737577

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 28 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_002890.3RefSeqNP_002881.125MANE Select
ENST00000274376.11EnsemblENSP00000274376.625MANE Select
NM_022650.3RefSeqNP_072179.125Standard
ENST00000456692.6EnsemblENSP00000411221.225Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / ModelOrganismObserved Phenotype
rasa1bDanio rerio

Structure: hindbrain

Quality: increased process quality

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Axon guidance - Homo sapiens (human)
  • Ras signaling pathway - Homo sapiens (human)
  • MAPK signaling pathway - Homo sapiens (human)
  • Androgen Receptor Network in Prostate Cancer
  • PDGF Pathway

Biological Process

  • MAPK cascade
  • mitotic cytokinesis
  • vasculogenesis
  • negative regulation of cell-matrix adhesion
  • negative regulation of cell adhesion

Molecular Function

  • phosphotyrosine residue binding
  • GTPase activity
  • GTPase activator activity
  • signaling receptor binding
  • protein binding

Cellular Component

  • ruffle
  • cytoplasm
  • cytosol
  • plasma membrane

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000274376
Coding exons
25
Length
124044
Individuals with no LoFs
125738
Homozygous LoFs
0
Heterozygous LoFs
10
Defined
125748
p
0.0000398
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense3.103695790.6380.00003026810
Missense (PolyPhen)114247.950.459772897
Synonymous-1.462262001.130.000009982044
Loss of Function6.83360.10.04990.00000345702

Population LoF Frequency

PopulationCAFp-valueStatus
African0.0000620.000062rare
Latino/Admixed American00.0absent
Ashkenazi Jewish00.0absent
East Asian0.000170.00016rare
Finnish00.0absent
European (Non-Finnish)0.0000530.000053rare
South Asian00.0absent
Other00.0absent

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Inhibitory regulator of the Ras-cyclic AMP pathway. Stimulates the GTPase of normal but not oncogenic Ras p21; this stimulation may be further increased in the presence of NCK1. {ECO:0000269|PubMed:11389730, ECO:0000269|PubMed:8360177}.;
Disease
DISEASE: Note=Mutations in the SH2 domain of RASA seem to be oncogenic and cause basal cell carcinomas.; DISEASE: Capillary malformation-arteriovenous malformation (CMAVM) [MIM:608354]: A disorder characterized by atypical capillary malformations that are multiple, small, round to oval in shape and pinkish red in color. These capillary malformations are associated with either arteriovenous malformation, arteriovenous fistula, or Parkes Weber syndrome. {ECO:0000269|PubMed:14639529, ECO:0000269|PubMed:24038909}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Parkes Weber syndrome (PKWS) [MIM:608355]: Disorder characterized by a cutaneous flush with underlying multiple micro- arteriovenous fistulas, in association with soft tissue and skeletal hypertrophy of the affected limb. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.135

Intolerance Scores

LoFtool
0.134
RVIS EVS
-0.82
RVIS percentile EVS
11.88

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.968

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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