USP33
protein-codingubiquitin specific peptidase 33, the group of Ubiquitin specific peptidases
Gene summary
This gene encodes a deubiquinating enzyme important in a variety of processes, including Slit-dependent cell migration and beta-2 adrenergic receptor signaling. The protein is negatively regulated through ubiquitination by von Hippel-Lindau tumor protein (VHL). Alternative splicing results in multiple transcript variants and protein isoforms. [provided by RefSeq, Jun 2012]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~63.9 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0001105
Submitter: PanelApp Australia
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to USP33 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_201624.3. 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 | 2 | 2 | ||||
| missense | 89 | 3 | 92 | |||
| nonsense | 1 | 1 | ||||
| start loss | 0 | |||||
| frameshift | 0 | |||||
| splice donor/acceptor (+/-2bp) | 6 | 6 | ||||
| Total | 0 | 0 | 98 | 3 | 0 | 101 |
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_963918.1 | 23 | MANE Select | |
| Ensembl | ENSP00000359830.3 | 23 | MANE Select | |
| RefSeq | NP_001364359.1 | 24 | Standard | |
| RefSeq | NP_001364360.1 | 23 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| usp33 | Danio rerio | Structure: post-vent region Quality: curled abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Developmental Biology
- Post-translational protein modification
- Metabolism of proteins
- Ub-specific processing proteases
- Deubiquitination
Biological Process
- ubiquitin-dependent protein catabolic process
- endocytosis
- axon guidance
- regulation of G protein-coupled receptor signaling pathway
- cellular response to starvation
Molecular Function
- G protein-coupled receptor binding
- cysteine-type endopeptidase activity
- thiol-dependent ubiquitin-specific protease activity
- protein binding
- zinc ion binding
Cellular Component
- nucleoplasm
- cytoplasm
- Golgi apparatus
- centrosome
- cytosol
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000370793
- Coding exons
- 24
- Length
- 63866
- Individuals with no LoFs
- 125725
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 20
- Defined
- 125745
- p
- 0.0000795
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 2.10 | 341 | 469 | 0.727 | 0.0000225 | 6223 |
| Missense (PolyPhen) | 99 | 195.68 | 0.50593 | 2649 | ||
| Synonymous | -0.425 | 168 | 161 | 1.04 | 0.00000840 | 1686 |
| Loss of Function | 5.50 | 11 | 55.0 | 0.200 | 0.00000285 | 685 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0.000061 | 0.000058 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.00011 | 0.00011 | rare |
| Finnish | 0.00014 | 0.00014 | rare |
| European (Non-Finnish) | 0.000071 | 0.000070 | rare |
| South Asian | 0.00018 | 0.00016 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Deubiquitinating enzyme involved in various processes such as centrosome duplication, cellular migration and beta-2 adrenergic receptor/ADRB2 recycling. Involved in regulation of centrosome duplication by mediating deubiquitination of CCP110 in S and G2/M phase, leading to stabilize CCP110 during the period which centrioles duplicate and elongate. Involved in cell migration via its interaction with intracellular domain of ROBO1, leading to regulate the Slit signaling. Plays a role in commissural axon guidance cross the ventral midline of the neural tube in a Slit-dependent manner, possibly by mediating the deubiquitination of ROBO1. Acts as a regulator of G-protein coupled receptor (GPCR) signaling by mediating the deubiquitination of beta-arrestins (ARRB1 and ARRB2) and beta-2 adrenergic receptor (ADRB2). Plays a central role in ADRB2 recycling and resensitization after prolonged agonist stimulation by constitutively binding ADRB2, mediating deubiquitination of ADRB2 and inhibiting lysosomal trafficking of ADRB2. Upon dissociation, it is probably transferred to the translocated beta- arrestins, leading to beta-arrestins deubiquitination and disengagement from ADRB2. This suggests the existence of a dynamic exchange between the ADRB2 and beta-arrestins. Deubiquitinates DIO2, thereby regulating thyroid hormone regulation. Mediates deubiquitination of both 'Lys-48'- and 'Lys-63'-linked polyubiquitin chains. {ECO:0000269|PubMed:12865408, ECO:0000269|PubMed:19363159, ECO:0000269|PubMed:19424180, ECO:0000269|PubMed:23486064}.;
Recessive Scores
- pRec
- 0.115
Intolerance Scores
- LoFtool
- 0.541
- RVIS EVS
- -1.44
- RVIS percentile EVS
- 3.96
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.758
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |