RASA2

protein-coding

RAS p21 protein activator 2, the group of C2 and RasGAP domain containing|Pleckstrin homology domain containing

Gene summary

The protein encoded by this gene is member 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. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2014]

MANE transcript

NM_006506.5

Inheritance

ClinVar variants

P:1U:518B:222

Top phenotype

Noonan syndrome

gnomAD constraint

pLI —, LoF o/e 0.94

Max pathogenic AF

—

Genomic locus

chr3:141,487,027-141,615,344

External References & Databases

Ensembl (ENSG00000155903)

Transcript & Mutation Effects

hg38 • Region Span ~128.3 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Noonan syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0018997

Submitter: Orphanet

Noonan syndromeLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0018997

Submitter: ClinGen

There has only been one study implicating RASA2 alteration with Noonan syndrome (NS) (Chen 2014). Three individuals with functionally characterized RASA2 variants of unknown origin and a Noonan syndrome phenotype have been identified (Chen et al., 2014). The RASA2 gene is also associated with the Ras/MAPK pathway which is associated with the NS phenotype (Aoki et al., 2016; Rauen, 2013). The ClinGen RASopathy Expert Panel found no evidence associating RASA2 with cardiofaciocutaneous syndrome, Costello syndrome, NS with loose anagen hair, or NS with multiple lentigines. In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This curation was approved by the ClinGen RASopathy Gene Curation Expert Panel on 7/24/18 (SOP Version 5).

Noonan syndromeMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0018997

Submitter: PanelApp Australia

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to RASA2 variants in ClinVar

6 Conditions Cataloged

not providedTotal: 660

not specifiedTotal: 508

RASA2-related disorderTotal: 42

Noonan syndromeTotal: 2

Noonan syndrome 1Total: 1

Hereditary cancer-predisposing syndromeTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_006506.5. 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			4 clinvar	201 clinvar		205
missense		1 clinvar	441 clinvar	19 clinvar	2 clinvar	463
nonsense			15 clinvar			15
start loss			1 clinvar			1
frameshift			26 clinvar			26
splice donor/acceptor (+/-2bp)			31 clinvar			31
Total	0	1	518	220	2	741

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 38 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_006506.5	RefSeq	NP_006497.2	24	MANE Select
ENST00000286364.9	Ensembl	ENSP00000286364.3	24	MANE Select
NM_001303245.3	RefSeq	NP_001290174.1	24	Standard
NM_001303246.3	RefSeq	NP_001290175.1	25	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Ras signaling pathway - Homo sapiens (human)
MAPK signaling pathway - Homo sapiens (human)
Viral carcinogenesis - Homo sapiens (human)
MAPK Signaling Pathway
Ebola Virus Pathway on Host

Biological Process

MAPK cascade
signal transduction
positive regulation of GTPase activity
negative regulation of Ras protein signal transduction

Molecular Function

GTPase activator activity
phospholipid binding
metal ion binding

Cellular Component

cytosol
perinuclear region of cytoplasm

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000286364
Coding exons: 24
Length: 128296
Individuals with no LoFs: 125664
Homozygous LoFs: 0
Heterozygous LoFs: 83
Defined: 125747
p: 0.000330

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.88	309	417	0.741	0.0000202	5590
Missense (PolyPhen)		80	123.23	0.6492		1668
Synonymous	-0.542	155	147	1.06	0.00000737	1515
Loss of Function	0.394	48	51.0	0.941	0.00000284	644

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00032	0.00031	rare
Latino/Admixed American	0.00059	0.00046	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00034	0.00033	rare
Finnish	0.00037	0.00037	rare
European (Non-Finnish)	0.00035	0.00034	rare
South Asian	0.00017	0.00016	rare
Other	0.00066	0.00065	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Inhibitory regulator of the Ras-cyclic AMP pathway. Binds inositol tetrakisphosphate (IP4).;

Recessive Scores

pRec: 0.115

Intolerance Scores

RVIS EVS: -0.69
RVIS percentile EVS: 15.2

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.405

Gene Damage Prediction

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