RASA1

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

Basic information

Region (hg38): 5:87267882-87391931

Previous symbols: [ "RASA" ]

Links

ENSG00000145715 ∙ NCBI:5921 ∙ OMIM:139150 ∙ HGNC:9871 ∙ Uniprot:P20936 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• telangiectasia, hereditary hemorrhagic, type 1 (No Known Disease Relationship), mode of inheritance: AD
• Parkes Weber syndrome (Limited), mode of inheritance: AD
• capillary malformation-arteriovenous malformation 1 (Limited), mode of inheritance: AD
• capillary malformation-arteriovenous malformation 1 (Strong), mode of inheritance: AD
• capillary malformation-arteriovenous malformation 1 (Definitive), mode of inheritance: AD
• Parkes Weber syndrome (Supportive), mode of inheritance: AD
• capillary malformation-arteriovenous malformation syndrome (Supportive), mode of inheritance: AD
• capillary malformation-arteriovenous malformation 1 (Strong), mode of inheritance: AD
• Noonan syndrome (Disputed Evidence), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Capillary malformation-arteriovenous malformation 1; Parkes Weber syndrome; Spinal arteriovenous anomalies	AD	Cardiovascular	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	Cardiovascular; Musculoskeletal	14639529; 15917201; 18363760; 18446851; 20007727; 21348050; 20821215; 22342634; 24038909

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the RASA1 gene.

• Capillary malformation-arteriovenous malformation syndrome (785 variants)
• Cardiovascular phenotype (205 variants)
• not provided (187 variants)
• Capillary malformation-arteriovenous malformation 1 (110 variants)
• Parkes Weber syndrome (48 variants)
• not specified (20 variants)
• RASA1-related condition (11 variants)
• Inborn genetic diseases (9 variants)
• Basal cell carcinoma, susceptibility to, 1;Capillary malformation-arteriovenous malformation 1 (9 variants)
• Capillary malformation-arteriovenous malformation 1;Basal cell carcinoma, susceptibility to, 1 (4 variants)
• Vascular malformation (2 variants)
• Capillary infantile hemangioma (1 variants)
• Gorham-Stout disease (1 variants)
• Hereditary hemorrhagic telangiectasia (1 variants)
• Basal cell carcinoma, susceptibility to, 1 (1 variants)
• See cases (1 variants)
• Hydrops fetalis;Cerebral venous angioma (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the RASA1 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			10	202		212
missense			337	19		356
nonsense	41	3	1			45
start loss						0
frameshift	72	8				80
inframe indel			12			12
splice donor/acceptor (+/-2bp)	13	26	3	1		43
splice region	1	3	28	29	5	66
non coding	2	3	25	151	35	216
Total	128	40	388	373	35

Highest pathogenic variant AF is 0.00000660

Variants in RASA1

This is a list of pathogenic ClinVar variants found in the RASA1 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
5-87267937-C-T			Likely benign (Jul 26, 2018)
5-87267958-C-CA			Benign (Jun 19, 2019)
5-87268153-T-G			Benign (Jul 26, 2018)
5-87268254-G-T		Capillary malformation-arteriovenous malformation 1 • Parkes Weber syndrome	Likely benign (Apr 10, 2019)
5-87268273-A-C		Capillary malformation-arteriovenous malformation 1 • Parkes Weber syndrome	Uncertain significance (Jan 12, 2018)
5-87268321-TTTG-T		Parkes Weber syndrome • Capillary malformation-arteriovenous malformation 1	Likely benign (Jun 14, 2016)
5-87268452-A-G		Capillary malformation-arteriovenous malformation syndrome	Uncertain significance (May 01, 2023)
5-87268463-C-A		Cardiovascular phenotype	Likely benign (Sep 17, 2021)
5-87268463-CGAGGCCGGCAGT-C		Capillary malformation-arteriovenous malformation syndrome	Uncertain significance (Jun 13, 2022)
5-87268463-CGAGGCCGGCAGTGAG-C		Capillary malformation-arteriovenous malformation syndrome	Uncertain significance (Oct 25, 2022)
5-87268468-C-T		Capillary malformation-arteriovenous malformation syndrome • Cardiovascular phenotype	Uncertain significance (Dec 19, 2023)
5-87268470-G-A		Cardiovascular phenotype	Uncertain significance (Aug 10, 2022)
5-87268470-G-C		Capillary malformation-arteriovenous malformation syndrome	Uncertain significance (Jan 18, 2023)
5-87268473-A-C		Cardiovascular phenotype	Uncertain significance (Jul 03, 2023)
5-87268473-AG-CT		Capillary malformation-arteriovenous malformation 1	Uncertain significance (Apr 15, 2019)
5-87268474-G-C		Capillary malformation-arteriovenous malformation syndrome	Uncertain significance (Sep 25, 2023)
5-87268474-G-T		Cardiovascular phenotype	Uncertain significance (Jul 03, 2023)
5-87268478-G-T		Capillary malformation-arteriovenous malformation syndrome • Cardiovascular phenotype	Uncertain significance (May 17, 2021)
5-87268480-A-T		Capillary malformation-arteriovenous malformation syndrome	Uncertain significance (Dec 30, 2023)
5-87268482-G-A		Capillary malformation-arteriovenous malformation syndrome	Uncertain significance (Nov 22, 2022)
5-87268485-G-A		Capillary malformation-arteriovenous malformation syndrome	Uncertain significance (Aug 24, 2023)
5-87268485-G-T		Capillary malformation-arteriovenous malformation syndrome	Uncertain significance (Nov 08, 2022)
5-87268487-C-T		Capillary malformation-arteriovenous malformation syndrome	Likely benign (Nov 20, 2022)
5-87268489-C-G		Capillary malformation-arteriovenous malformation syndrome	Uncertain significance (Dec 01, 2023)
5-87268490-G-A		Cardiovascular phenotype	Likely benign (Oct 02, 2022)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
RASA1	protein_coding	protein_coding	ENST00000274376	25	124044

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.00	4.36e-8	125738	0	10	125748	0.0000398

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	3.10	369	579	0.638	0.0000302	6810
Missense in Polyphen		114	247.95	0.45977		2897
Synonymous	-1.46	226	200	1.13	0.00000998	2044
Loss of Function	6.83	3	60.1	0.0499	0.00000345	702

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.0000617	0.0000615
Ashkenazi Jewish	0.00	0.00
East Asian	0.000165	0.000163
Finnish	0.00	0.00
European (Non-Finnish)	0.0000530	0.0000527
Middle Eastern	0.000165	0.000163
South Asian	0.00	0.00
Other	0.00	0.00

dbNSFP

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.
• Pathway: 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;T-Cell Receptor and Co-stimulatory Signaling;Signaling of Hepatocyte Growth Factor Receptor;Rac1-Pak1-p38-MMP-2 pathway;MAPK Signaling Pathway;PDGFR-beta pathway;Ras Signaling;EGF-EGFR Signaling Pathway;EPO Receptor Signaling;Developmental Biology;Signaling by PTK6;Regulation of Ras family activation;Signal Transduction;regulation of splicing through sam68;egf signaling pathway;hiv-1 nef: negative effector of fas and tnf;VEGFA-VEGFR2 Pathway;sprouty regulation of tyrosine kinase signals;Signaling by PDGF;igf-1 signaling pathway;EPH-Ephrin signaling;TCR;EPHB-mediated forward signaling;Regulation of RAS by GAPs;KitReceptor;BCR;Aurora A signaling;pdgf signaling pathway;tpo signaling pathway;EGFR1;RAF/MAP kinase cascade;MAPK1/MAPK3 signaling;MAPK family signaling cascades;BCR signaling pathway;PDGF;PTK6 Regulates RHO GTPases, RAS GTPase and MAP kinases;Signaling by Non-Receptor Tyrosine Kinases;Signaling events regulated by Ret tyrosine kinase;IL2-mediated signaling events;Downstream signal transduction;Signaling by VEGF;Angiopoietin receptor Tie2-mediated signaling;Axon guidance;Signaling by Receptor Tyrosine Kinases;Insulin Pathway;Neurotrophic factor-mediated Trk receptor signaling;Aurora B signaling;Fc-epsilon receptor I signaling in mast cells;Signaling events mediated by focal adhesion kinase;EPHB forward signaling;PDGFR-beta signaling pathway;Syndecan-2-mediated signaling events;VEGFR1 specific signals;VEGFR2 mediated cell proliferation (Consensus)

Recessive Scores

• pRec: 0.135

Intolerance Scores

• loftool: 0.134
• rvis_EVS: -0.82
• rvis_percentile_EVS: 11.88

Haploinsufficiency Scores

• pHI: 0.716
• hipred: Y
• hipred_score: 0.783
• ghis: 0.644

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.968

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Rasa1
• Phenotype: skeleton phenotype; immune system phenotype; hearing/vestibular/ear phenotype; nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); limbs/digits/tail phenotype; digestive/alimentary phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); embryo phenotype; cellular phenotype; craniofacial phenotype; muscle phenotype; growth/size/body region phenotype

Zebrafish Information Network

• Gene name: rasa1b
• Affected structure: hindbrain
• Phenotype tag: abnormal
• Phenotype quality: increased process quality

Gene ontology

• Biological process: MAPK cascade;mitotic cytokinesis;vasculogenesis;negative regulation of cell-matrix adhesion;negative regulation of cell adhesion;signal transduction;regulation of cell shape;regulation of actin filament polymerization;intracellular signal transduction;negative regulation of apoptotic process;negative regulation of neuron apoptotic process;positive regulation of GTPase activity;negative regulation of Ras protein signal transduction;ephrin receptor signaling pathway;blood vessel morphogenesis;regulation of RNA metabolic process
• Cellular component: ruffle;cytoplasm;cytosol;plasma membrane
• Molecular function: phosphotyrosine residue binding;GTPase activity;GTPase activator activity;signaling receptor binding;protein binding;potassium channel inhibitor activity;GTPase binding