RASAL1

protein-coding

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

Gene summary

The protein encoded by this gene is member of the GAP1 family of GTPase-activating proteins. These proteins stimulate 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. This particular family member contains domains which are characteristic of the GAP1 subfamily of RasGAP proteins but, in contrast to the other GAP1 family members, this protein is strongly and selectively expressed in endocrine tissues. Alternatively spliced transcript variants that encode different isoforms have been described [provided by RefSeq, Jul 2010]

MANE transcript

NM_001301202.2

Inheritance

ClinVar variants

U:157B:22

Top phenotype

Hereditary cancer

gnomAD constraint

pLI —, LoF o/e 0.7

Max pathogenic AF

—

Genomic locus

chr12:113,098,819-113,136,239

External References & Databases

Ensembl (ENSG00000111344)

Transcript & Mutation Effects

hg38 • Region Span ~37.4 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

breast cancerLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0007254

Submitter: Ambry Genetics

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to RASAL1 variants in ClinVar

3 Conditions Cataloged

not specifiedTotal: 149

not providedTotal: 15

Hereditary cancerTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001301202.2. 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			1 clinvar	5 clinvar	5 clinvar	11
missense			150 clinvar	10 clinvar	2 clinvar	162
nonsense			1 clinvar			1
start loss						0
frameshift			1 clinvar			1
splice donor/acceptor (+/-2bp)			4 clinvar			4
Total	0	0	157	15	7	179

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 57 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001301202.2	RefSeq	NP_001288131.1	21	MANE Select
ENST00000548055.2	Ensembl	ENSP00000448510.1	21	MANE Select
NM_001193520.2	RefSeq	NP_001180449.1	21	Standard
NM_001193521.3	RefSeq	NP_001180450.1	21	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Ras signaling pathway - Homo sapiens (human)
Ras Signaling
Regulation of Ras family activation
Signal Transduction
Regulation of RAS by GAPs

Biological Process

MAPK cascade
signal transduction
positive regulation of GTPase activity
negative regulation of Ras protein signal transduction
cellular response to calcium ion

Molecular Function

GTPase activator activity
phospholipid binding
metal ion binding

Cellular Component

cytosol
plasma membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000546530
Coding exons: 21
Length: 37421
Individuals with no LoFs: 125654
Homozygous LoFs: 0
Heterozygous LoFs: 94
Defined: 125748
p: 0.000374

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.757	420	466	0.901	0.0000283	5158
Missense (PolyPhen)		145	162.82	0.89055		1796
Synonymous	1.57	159	186	0.854	0.0000104	1649
Loss of Function	1.79	28	40.3	0.695	0.00000204	449

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00012	0.00012	rare
Latino/Admixed American	0.00031	0.00029	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0.00083	0.00082	rare
Finnish	0.000092	0.000092	rare
European (Non-Finnish)	0.00030	0.00029	rare
South Asian	0.00095	0.00095	rare
Other	0.00035	0.00033	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Probable inhibitory regulator of the Ras-cyclic AMP pathway (PubMed:9751798). Plays a role in dendrite formation by melanocytes (PubMed:23999003). {ECO:0000269|PubMed:23999003, ECO:0000269|PubMed:9751798}.;

Recessive Scores

pRec: 0.0953

Intolerance Scores

LoFtool: 0.862
RVIS EVS: 0.47
RVIS percentile EVS: 78.85

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.209

Gene Damage Prediction

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