RAB28

protein-coding

RAB28, member RAS oncogene family, the group of RAB, member RAS oncogene GTPases

Gene summary

This gene encodes a member of the Rab subfamily of Ras-related small GTPases. The encoded protein may be involved in regulating intracellular trafficking. Alternative splicing results in multiple transcript variants. Pseudogenes of this gene are found on chromosomes 9 and X. [provided by RefSeq, Apr 2009]

MANE transcript

NM_001017979.3

Inheritance

AR, AD

ClinVar variants

P:24U:80B:36

Top phenotype

Cone-rod dystrophy 18

gnomAD constraint

pLI —, LoF o/e 0.36

Max pathogenic AF

—

Genomic locus

chr4:13,361,354-13,484,365

External References & Databases

Ensembl (ENSG00000157869)

Transcript & Mutation Effects

hg38 • Region Span ~123.0 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

cone-rod dystrophy 18STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014153

Submitter: PanelApp Australia

RAB28-related retinopathyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0100448

Submitter: ClinGen

RAB28 was first reported in relation to autosomal recessive cone-rod dystrophy in 2013 (Roosing et al, PMID 23746546). Autosomal recessive cone-rod dystrophies are a group of inherited retinal disorders involving primary loss of cone photoreceptors with subsequent loss of rods. Clinical symptoms include severely reduced visual acuity, impaired color vision, photophobia, atrophy in the macular region, and reduced cone responses observed on electroretinography. The disease entity curated was RAB28-related retinopathy which encompasses the phenotypes associated with this gene. Ten variants in RAB28 (missense, splicing, nonsense) from ten probands with cone-rod dystrophy have been reported and are included in this curation (Roosing et al, 2013, PMID 23746546; Riveiro-Álvarez et al, 2015, PMID 25356532; Lee et al, 2017, PMID 28388261; Iarossi et al, 2020, PMID 33396523; Jespersgaard et al, 2020, PMID 32084271). The maximum points for genetic evidence (12 points) has been reached. The mechanism of pathogenicity appears to be loss of function. This gene-disease relationship is also supported by experimental evidence. RAB28 is a member of the RAB subfamily of the RAS oncogene family of Ras-related small GTPases and has been reported to have a role in intraflaggelar transport and extracellular vesicle formation in C.elegans ciliated neurons, where it is targeted to the periciliary membrane by the BBSome (Jensen et al, 2016, PMID 27930654; Akella et al, 2020). Features reported in a Rab28 null mouse (Ying et al, 2018, PMID 30228185) and zebrafish model (Carter et al, 2020, PMID 32258030), including defective cone outer segment phagocytosis, support the relationship between RAB28 and cone-rod dystrophy. In summary, RAB28 is definitively associated with autosomal recessive RAB28-related retinopathy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.

cone-rod dystrophy 18DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014153

Submitter: G2P

cone-rod dystrophySUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0015993

Submitter: Orphanet

cone-rod dystrophy 18STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014153

Submitter: Labcorp Genetics (formerly Invitae)

cone-rod dystrophy 18MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0014153

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Cone-rod dystrophy 18AR

Manifestation: 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: 23746546; 25356532

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to RAB28 variants in ClinVar

9 Conditions Cataloged

not providedTotal: 194

not specifiedTotal: 36

RAB28-related disorderTotal: 14

Cone-rod dystrophy 18Total: 11

Retinal dystrophyTotal: 7

Cone-rod dystrophyTotal: 2

Optic atrophyTotal: 1

Cone dystrophyTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001017979.3. 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			1 clinvar	35 clinvar		36
missense		5 clinvar	75 clinvar	1 clinvar		81
nonsense	2 clinvar	1 clinvar	2 clinvar			5
start loss		1 clinvar				1
frameshift	5 clinvar	7 clinvar	1 clinvar			13
splice donor/acceptor (+/-2bp)	1 clinvar	2 clinvar	1 clinvar			4
Total	8	16	80	36	0	140

Highest pathogenic variant AF is 0.000015528085

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 60 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001017979.3	RefSeq	NP_001017979.1	7	MANE Select
ENST00000330852.10	Ensembl	ENSP00000328551.5	7	MANE Select
NM_001159601.2	RefSeq	NP_001153073.1	7	Standard
NM_004249.4	RefSeq	NP_004240.2	7	MANE Plus Clinical

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

intracellular protein transport
Rab protein signal transduction
toxin transport

Molecular Function

GTPase activity
GTP binding
GDP binding

Cellular Component

cytoplasm
plasma membrane
ciliary rootlet
ciliary basal body

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000330852
Coding exons: 7
Length: 123012
Individuals with no LoFs: 125722
Homozygous LoFs: 0
Heterozygous LoFs: 25
Defined: 125747
p: 0.0000994

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.377	101	112	0.900	0.00000522	1442
Missense (PolyPhen)		35	36.331	0.96337		480
Synonymous	-0.224	42	40.2	1.04	0.00000195	391
Loss of Function	2.20	5	13.8	0.362	6.68e-7	171

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00025	0.00025	rare
Latino/Admixed American	0.00012	0.00012	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00011	0.00011	rare
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.00013	0.00012	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Recessive Scores

pRec: 0.108

Intolerance Scores

LoFtool: 0.789
RVIS EVS: -0.23
RVIS percentile EVS: 36.86

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.307

Gene Damage Prediction

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