RAB33B

protein-coding

RAB33B, member RAS oncogene family, the group of RAB, member RAS oncogene GTPases

Gene summary

This gene encodes a small GTP-binding protein of the Rab GTPase family, whose members function in vesicle transport during protein secretion and endocytosis. Rab GTPases are active, membrane-associated proteins that recruit effector proteins in the GTP-bound state and inactive cytosolic proteins when in a GDP-bound state. The protein encoded by this gene is ubiquitously expressed and has been implicated in Golgi to endoplasmic reticulum cycling of Golgi enzymes. In addition, this protein regulates Golgi homeostasis and coordinates intra-Golgi retrograde trafficking. Allelic variants in this gene have been associated with Dyggve-Melchior-Clausen syndrome and Smith-McCort dysplasia 2, which are autosomal recessive spondyloepimetaphyseal dysplasias characterized by skeletal abnormalities. [provided by RefSeq, Sep 2016]

MANE transcript

NM_031296.3

Inheritance

ClinVar variants

P:14U:42B:29

Top phenotype

Dyggve-Melchior-Clausen syndrome; Smith-McCort dysplasia 2

gnomAD constraint

pLI —, LoF o/e 0.13

Max pathogenic AF

—

Genomic locus

chr4:139,453,232-139,476,609

External References & Databases

Ensembl (ENSG00000172007)

Transcript & Mutation Effects

hg38 • Region Span ~23.4 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Smith-McCort dysplasiaSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0015799

Submitter: Orphanet

Smith-McCort dysplasia 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014087

Submitter: Labcorp Genetics (formerly Invitae)

Smith-McCort dysplasia 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014087

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Dyggve-Melchior-Clausen syndrome; Smith-McCort dysplasia 2AR

Manifestation: Musculoskeletal; Neurologic

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: 22652534; 23042644

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to RAB33B variants in ClinVar

6 Conditions Cataloged

not providedTotal: 59

Smith-McCort dysplasia 2Total: 29

Inborn genetic diseasesTotal: 20

not specifiedTotal: 3

See casesTotal: 1

RAB33B-related disorderTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_031296.3. 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			3 clinvar	23 clinvar	2 clinvar	28
missense	1 clinvar	2 clinvar	37 clinvar	4 clinvar		44
nonsense	6 clinvar	1 clinvar	2 clinvar			9
start loss						0
frameshift	2 clinvar	2 clinvar				4
splice donor/acceptor (+/-2bp)						0
Total	9	5	42	27	2	85

Highest pathogenic variant AF is 0.000008710368

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 7 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_031296.3	RefSeq	NP_112586.1	2	MANE Select
ENST00000305626.6	Ensembl	ENSP00000306496.5	2	MANE Select
ENST00000652268.1	Ensembl	ENSP00000498778.1	3	Standard
ENST00000873886.1	Ensembl	ENSP00000543945.1	2	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Autophagy - animal - Homo sapiens (human)
Vesicle-mediated transport
TBC/RABGAPs
Membrane Trafficking
Post-translational protein modification

Biological Process

autophagosome assembly
regulation of cell growth
intracellular protein transport
endoplasmic reticulum to Golgi vesicle-mediated transport
intra-Golgi vesicle-mediated transport

Molecular Function

GTPase activity
protein binding
GTP binding

Cellular Component

Golgi membrane
endoplasmic reticulum membrane
Golgi apparatus
Golgi lumen
presynapse

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000305626
Coding exons: 2
Length: 23378
Individuals with no LoFs: 125551
Homozygous LoFs: 0
Heterozygous LoFs: 3
Defined: 125554
p: 0.0000119

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.629	112	132	0.846	0.00000622	1523
Missense (PolyPhen)		37	58.833	0.6289		684
Synonymous	-1.02	59	49.9	1.18	0.00000250	440
Loss of Function	2.28	1	7.95	0.126	4.51e-7	82

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000058	0.000058	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0	0.0	absent
South Asian	0.000033	0.000033	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Protein transport. Acts, in coordination with RAB6A, to regulate intra-Golgi retrograde trafficking. It is involved in autophagy, acting as a modulator of autophagosome formation. {ECO:0000269|PubMed:20163571}.;
Disease: DISEASE: Smith-McCort dysplasia 2 (SMC2) [MIM:615222]: A rare autosomal recessive osteochondrodysplasia with skeletal features identical to those of Dyggve-Melchior-Clausen syndrome, but with normal intelligence and no microcephaly. It is characterized by short limbs and trunk with barrel-shaped chest. The radiographic phenotype includes platyspondyly, generalized abnormalities of the epiphyses and metaphyses, and a distinctive lacy appearance of the iliac crest. {ECO:0000269|PubMed:22652534, ECO:0000269|PubMed:23042644}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.108

Intolerance Scores

LoFtool: 0.0900
RVIS EVS: 0.08
RVIS percentile EVS: 60.09

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.781

Gene Damage Prediction

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