VPS33B
protein-codingVPS33B late endosome and lysosome associated
Gene summary
Vesicle mediated protein sorting plays an important role in segregation of intracellular molecules into distinct organelles. Genetic studies in yeast have identified more than 40 vacuolar protein sorting (VPS) genes involved in vesicle transport to vacuoles. This gene is a member of the Sec-1 domain family, and encodes the human ortholog of rat Vps33b which is homologous to the yeast class C Vps33 protein. The mammalian class C vacuolar protein sorting proteins are predominantly associated with late endosomes/lysosomes, and like their yeast counterparts, may mediate vesicle trafficking steps in the endosome/lysosome pathway. Mutations in this gene are associated with arthrogryposis-renal dysfunction-cholestasis syndrome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2014]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~23.9 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0008822
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0008822
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0017123
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0008822
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0859278
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0008822
Submitter: ClinGen
VPS33B was first reported in relation to autosomal recessive arthrogryposis, renal dysfunction, and cholestasis 1 (ARC) in 2004 (Gissen P, et al., 2004, PMID: 15052268). The classical presentation of ARC includes congenital joint contractures, renal tubular dysfunction, and cholestasis. Additional features include ichthyosis, central nervous system malformation, platelet anomalies, and severe failure to thrive. At least 19 unique variants (mostly nonsense but also frameshift, splicing, start loss, and missense) have been reported in humans with Pathogenic classifications in ClinVar. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in at least 9 probands in 2 publications (PMIDs: 15052268, 18853461), included in this curation. Additional evidence is available in the literature, however the maximum points for genetic evidence were reached. This gene-disease relationship is supported by its interaction with VIPAS39 (PMID: 20190753) and their function as part of a complex that interacts with an active form of RAB11A involved in apical membrane protein sorting, the alteration in mIMCD-3 cells confirming the role of VPS33B in regulating apical-basolateral polarity in the kidney consistent with the renal dysfunction seen in patients (PMID: 20190753), a zebrafish model recapitulating biliary abnormalities (PMID: 20190753), and a mouse model with collagen abnormalities identified in skin fibroblasts and tendons consistent with the characteristic ARC features of ichthyosis, arthrogryposis, osteopenia and bone fractures (PMID: 27435297) as well as a marked reduction in α-granule count and the presence of small granule-like structures in agreement with the platelet phenotype observed in ARC patients (PMID: 25947942). In summary VPS33B is definitively associated with autosomal recessive arthrogryposis, renal dysfunction, and cholestasis 1.
Clinical Genomic Database (CGD)
Manifestation: Audiologic/Otolaryngologic; Cardiovascular; Craniofacial; Dermatologic; Gastrointestinal; Musculoskeletal; Renal
Intervention: Audiologic/Otolaryngologic; Cardiovascular; Gastrointestinal; Renal
Rationale: Individuals with Keratoderma-ichthyosis-deafness syndrome, autosomal recessive have been described with hearing impairment, and early recognition and treatment of hearing impairment may improve outcomes, including speech and language development; Cholestasis, progressive familial intrahepatic has been described as involving early-onset hepatic dysfunction, and medical and surgical interventions have been described as beneficial in some individuals; Individuals with Arthrogryposis, renal dysfunction, and cholestasis 1 may have manifstations including hearing loss, cardiovascular anomalies, renal dysfunction, and cholestasis, and awareness may allow early diagnosis and medical or surgical management of these sequelae
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to VPS33B variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_018668.5. 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 | 2 | 8 | 67 | 5 | 83 |
| missense | 3 | 3 | 213 | 8 | 227 | |
| nonsense | 10 | 5 | 1 | 16 | ||
| start loss | 0 | |||||
| frameshift | 9 | 10 | 2 | 21 | ||
| splice donor/acceptor (+/-2bp) | 8 | 13 | 9 | 30 | ||
| Total | 31 | 33 | 233 | 75 | 5 | 377 |
Highest pathogenic variant AF is 0.000018588029
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_061138.3 | 23 | MANE Select | |
| Ensembl | ENSP00000327650.4 | 23 | MANE Select | |
| RefSeq | NP_001276077.1 | 22 | Standard | |
| RefSeq | NP_001276078.1 | 20 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| vps33b | Danio rerio | Structure: enterocyte Quality: dilated abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Biological Process
- vesicle docking involved in exocytosis
- endosome organization
- endosome to lysosome transport
- protein transport
- vesicle-mediated transport
Molecular Function
- protein binding
Cellular Component
- cytoplasm
- lysosome
- lysosomal membrane
- late endosome
- Golgi apparatus
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000333371
- Coding exons
- 23
- Length
- 24188
- Individuals with no LoFs
- 125653
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 95
- Defined
- 125748
- p
- 0.000378
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.364 | 314 | 333 | 0.944 | 0.0000205 | 4057 |
| Missense (PolyPhen) | 99 | 113.1 | 0.87533 | 1287 | ||
| Synonymous | 0.320 | 120 | 125 | 0.964 | 0.00000696 | 1149 |
| Loss of Function | 1.76 | 31 | 43.5 | 0.712 | 0.00000282 | 477 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00018 | 0.00018 | rare |
| Latino/Admixed American | 0.00061 | 0.00061 | rare |
| Ashkenazi Jewish | 0.00079 | 0.00079 | rare |
| East Asian | 0.00049 | 0.00049 | rare |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.00039 | 0.00039 | rare |
| South Asian | 0.00020 | 0.00020 | rare |
| Other | 0.00065 | 0.00065 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: May play a role in vesicle-mediated protein trafficking to lysosomal compartments and in membrane docking/fusion reactions of late endosomes/lysosomes. Mediates phagolysosomal fusion in macrophages (PubMed:18474358). Proposed to be involved in endosomal maturation implicating VIPAS39. In epithelial cells, the VPS33B:VIPAS39 complex may play a role in the apical recycling pathway and in the maintenance of the apical-basolateral polarity (PubMed:20190753). Seems to be involved in the sorting of specific cargos from the trans-Golgi network to alpha-granule-destined multivesicular bodies (MVBs) promoting MVBs maturation in megakaryocytes (By similarity). {ECO:0000250|UniProtKB:P59016, ECO:0000269|PubMed:18474358, ECO:0000305|PubMed:20190753, ECO:0000305|PubMed:23918659}.;
- Disease
- DISEASE: Arthrogryposis, renal dysfunction and cholestasis syndrome 1 (ARCS1) [MIM:208085]: A multisystem disorder, characterized by neurogenic arthrogryposis multiplex congenita, renal tubular dysfunction and neonatal cholestasis with bile duct hypoplasia and low gamma glutamyl transpeptidase activity. Platelet dysfunction is common. {ECO:0000269|PubMed:15052268, ECO:0000269|PubMed:18853461, ECO:0000269|PubMed:20190753, ECO:0000269|PubMed:22753090, ECO:0000269|PubMed:23918659}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.118
Intolerance Scores
- LoFtool
- 0.822
- RVIS EVS
- -0.53
- RVIS percentile EVS
- 20.82
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.789
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |