RAB3GAP1

protein-coding

RAB3 GTPase activating protein catalytic subunit 1

Gene summary

This gene encodes the catalytic subunit of a Rab GTPase activating protein. The encoded protein forms a heterodimer with a non-catalytic subunit to specifically regulate the activity of members of the Rab3 subfamily of small G proteins. This protein mediates the hydrolysis of GTP bound Rab3 to the GDP bound form. Mutations in this gene are associated with Warburg micro syndrome. Alternate splicing results in multiple transcript variants.[provided by RefSeq, Feb 2010]

MANE transcript

NM_012233.3

Inheritance

ClinVar variants

P:87U:234B:99

Top phenotype

Warburg micro syndrome 1

gnomAD constraint

pLI —, LoF o/e 0.38

Max pathogenic AF

—

Genomic locus

chr2:135,052,289-135,176,667

External References & Databases

Ensembl (ENSG00000115839)

Transcript & Mutation Effects

hg38 • Region Span ~124.4 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

cataract-intellectual disability-hypogonadism syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0008929

Submitter: Orphanet

Warburg micro syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0016649

Submitter: Orphanet

Warburg micro syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0016649

Submitter: ClinGen

RAB3GAP1 was reported in relation to Warburg Micro Syndrome in 2005 (PMID: 15696165). Evidence supporting this gene-disease relationship is largely case-level data. Variants in this gene have been reported across many publications (PMID: 25326635, 20512159, 23420520, 26421802). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) was reached. However, functional assays have not been done for this gene and would provide an area of interest for future publication. The mechanism for disease is loss of function. In summary, RAB3GAP1 is definitively associated with Warburg Micro Syndrome.

Warburg micro syndrome 1STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0010822

Submitter: Labcorp Genetics (formerly Invitae)

Warburg micro syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0016649

Submitter: PanelApp Australia

Warburg micro syndrome 1DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0010822

Submitter: G2P

Clinical Genomic Database (CGD)

Warburg micro syndrome 1AR

Manifestation: Craniofacial; Endocrine; Genitourinary; Musculoskeletal; Neurologic; Ophthalmologic

Intervention: Endocrine; Ophthalmologic; Pharmacogenomic

Rationale: The condition can include a risk of glaucoma, and early treatment may be beneficial; Medical care related to endocrine manifestations may be indicated; Agents that may contribute to glaucoma should be avoided

Refs: 8249951; 10465117; 11237903; 15216543; 15696165; 18286824; 20512159; 22768674; 23420520; 30730599

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to RAB3GAP1 variants in ClinVar

29 Conditions Cataloged

not providedTotal: 377

Inborn genetic diseasesTotal: 124

Warburg micro syndrome 1Total: 101

not specifiedTotal: 49

RAB3GAP1-related disorderTotal: 47

Martsolf syndrome 2Total: 24

Structural eye diseaseTotal: 2

AmenorrheaTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_012233.3. 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			11 clinvar	76 clinvar	4 clinvar	91
missense	2 clinvar	1 clinvar	210 clinvar	16 clinvar	3 clinvar	232
nonsense	24 clinvar	8 clinvar	1 clinvar			33
start loss						0
frameshift	18 clinvar	15 clinvar	1 clinvar			34
splice donor/acceptor (+/-2bp)	9 clinvar	10 clinvar	11 clinvar			30
Total	53	34	234	92	7	420

Highest pathogenic variant AF is 0.000029136807

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 45 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_012233.3	RefSeq	NP_036365.1	24	MANE Select
ENST00000264158.13	Ensembl	ENSP00000264158.8	24	MANE Select
NM_001172435.2	RefSeq	NP_001165906.1	25	Standard
ENST00000425393.1	Ensembl	ENSP00000400761.1	3	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Vesicle-mediated transport
Membrane Trafficking
Rab regulation of trafficking
COPI-independent Golgi-to-ER retrograde traffic
Golgi-to-ER retrograde transport

Biological Process

brain development
positive regulation of gene expression
hypothalamus development
lipid droplet organization
camera-type eye development

Molecular Function

guanyl-nucleotide exchange factor activity
GTPase activator activity
protein binding
Rab guanyl-nucleotide exchange factor activity
Rab GTPase binding

Cellular Component

endoplasmic reticulum membrane
Golgi apparatus
lipid droplet
cytosol
protein-containing complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000442034
Coding exons: 25
Length: 124130
Individuals with no LoFs: 125652
Homozygous LoFs: 0
Heterozygous LoFs: 96
Defined: 125748
p: 0.000382

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.18	440	516	0.853	0.0000269	6458
Missense (PolyPhen)		114	146.23	0.77959		1693
Synonymous	0.266	177	182	0.975	0.00000928	1877
Loss of Function	4.50	23	60.9	0.378	0.00000336	714

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00055	0.00055	rare
Latino/Admixed American	0.00029	0.00029	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0.00027	0.00027	rare
Finnish	0.00074	0.00074	rare
European (Non-Finnish)	0.00041	0.00040	rare
South Asian	0.00029	0.00029	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Probable catalytic subunit of a GTPase activating protein that has specificity for Rab3 subfamily (RAB3A, RAB3B, RAB3C and RAB3D). Rab3 proteins are involved in regulated exocytosis of neurotransmitters and hormones. Specifically converts active Rab3-GTP to the inactive form Rab3-GDP. Required for normal eye and brain development. May participate in neurodevelopmental processes such as proliferation, migration and differentiation before synapse formation, and non-synaptic vesicular release of neurotransmitters. {ECO:0000269|PubMed:10859313, ECO:0000269|PubMed:9030515}.;

Recessive Scores

pRec: 0.149

Intolerance Scores

LoFtool: 0.941
RVIS EVS: 0.2
RVIS percentile EVS: 67.43

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.673

Gene Damage Prediction

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