RAB18

protein-coding

RAB18, member RAS oncogene family, the group of RAB, member RAS oncogene GTPases

Gene summary

The protein encoded by this gene is a member of a family of Ras-related small GTPases that regulate membrane trafficking in organelles and transport vesicles. Knockdown studies is zebrafish suggest that this protein may have a role in eye and brain development. Mutations in this gene are associated with Warburg micro syndrome type 3. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Jan 2012]

MANE transcript

NM_021252.5

Inheritance

ClinVar variants

P:6U:48B:20

Top phenotype

Warburg micro syndrome 3

gnomAD constraint

pLI —, LoF o/e 0.08

Max pathogenic AF

—

Genomic locus

chr10:27,504,174-27,545,117

External References & Databases

Ensembl (ENSG00000099246)

Transcript & Mutation Effects

hg38 • Region Span ~40.9 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Warburg micro syndrome 3STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013638

Submitter: Labcorp Genetics (formerly Invitae)

Warburg micro syndrome 3DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013638

Submitter: G2P

Warburg micro syndromeMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0016649

Submitter: ClinGen

RAB18 was originally reported in cases of Warburg Micro syndrome in 2011 (PMID: 21473985). This initial report included 9 individuals with p.Leu24Gln, which is shown to lose the ability to bind GDP and GTP, suggesting a loss-of-function. They are from 4 families, which are from the same geographical region and share the same ancestral haplotype, and one proband was scored. This and another paper (PMID: 23420520) reported 4 additional individuals from 3 families with different mutations, and one proband from each family was scored. A mouse brain expression study (PMID: 26879639), two independent knockout mouse models (PMID: 24764192, 25779931) and zebrafish morpholino knockdown study (PMID: 21473985) were scored as functional evidence. In total, it was interpreted that there is moderate level of evidence to suggest that RAB18 is associated with Warburg Micro syndrome. This curation was approved by the Brain Malformation Panel on 9/13/2022.

Warburg micro syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0016649

Submitter: Orphanet

Warburg micro syndrome 3STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013638

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Warburg micro syndrome 3AR

Manifestation: Craniofacial; Musculoskeletal; Neurologic; Ophthalmologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 21473985

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to RAB18 variants in ClinVar

5 Conditions Cataloged

not providedTotal: 51

Inborn genetic diseasesTotal: 23

Warburg micro syndrome 3Total: 18

RAB18-related disorderTotal: 10

not specifiedTotal: 9

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_021252.5. 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			1 clinvar	17 clinvar		18
missense	2 clinvar	1 clinvar	39 clinvar	2 clinvar	1 clinvar	45
nonsense						0
start loss						0
frameshift	1 clinvar	2 clinvar	1 clinvar			4
splice donor/acceptor (+/-2bp)			7 clinvar			7
Total	3	3	48	19	1	74

Highest pathogenic variant AF is 0.000008059216

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 47 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_021252.5	RefSeq	NP_067075.1	7	MANE Select
ENST00000356940.11	Ensembl	ENSP00000349415.7	7	MANE Select
NM_001256410.2	RefSeq	NP_001243339.1	8	Standard
NM_001256411.2	RefSeq	NP_001243340.1	6	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
rab18b	Danio rerio	Structure: iridophore Quality: decreased amount abnormal

Gene / Model

Organism

Observed Phenotype

rab18b

Danio rerio

Structure: iridophore

Quality: decreased amount

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Neutrophil degranulation
Vesicle-mediated transport
Membrane Trafficking
Post-translational protein modification
Metabolism of proteins

Biological Process

eye development
intracellular protein transport
small GTPase mediated signal transduction
brain development
Rab protein signal transduction

Molecular Function

GTPase activity
protein binding
GTP binding
GDP binding

Cellular Component

endoplasmic reticulum membrane
Golgi apparatus
cytosol
plasma membrane
secretory granule membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000356940
Coding exons: 7
Length: 37947
Individuals with no LoFs: 125697
Homozygous LoFs: 0
Heterozygous LoFs: 6
Defined: 125703
p: 0.0000239

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.39	68	109	0.625	0.00000511	1342
Missense (PolyPhen)		25	42.709	0.58536		539
Synonymous	-0.297	42	39.6	1.06	0.00000198	382
Loss of Function	2.96	1	12.2	0.0823	6.10e-7	147

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00012	0.00012	rare
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000054	0.000054	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.000026	0.000026	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Plays a role in apical endocytosis/recycling. May be implicated in transport between the plasma membrane and early endosomes. Plays a key role in eye and brain development and neurodegeneration. {ECO:0000269|PubMed:21473985}.;

Recessive Scores

pRec: 0.110

Intolerance Scores

LoFtool: 0.541
RVIS EVS: 0.1
RVIS percentile EVS: 61.28

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): H
Indispensability pred.: E
Indispensability score: 0.961