USP4
protein-codingubiquitin specific peptidase 4, the group of Ubiquitin specific peptidases
Gene summary
The protein encoded by this gene is a protease that deubiquitinates target proteins such as ADORA2A and TRIM21. The encoded protein shuttles between the nucleus and cytoplasm and is involved in maintaining operational fidelity in the endoplasmic reticulum. Three transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2011]
- UNP
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~63.6 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
No GenCC data available for this gene.
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to USP4 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_003363.4. 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 | 6 | 7 | |||
| missense | 120 | 3 | 2 | 125 | ||
| nonsense | 1 | 1 | ||||
| start loss | 0 | |||||
| frameshift | 0 | |||||
| splice donor/acceptor (+/-2bp) | 5 | 5 | ||||
| Total | 0 | 0 | 127 | 9 | 2 | 138 |
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_003354.2 | 22 | MANE Select | |
| Ensembl | ENSP00000265560.4 | 22 | MANE Select | |
| RefSeq | NP_001238806.1 | 7 | Standard | |
| RefSeq | NP_955475.1 | 21 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| usp4 | Danio rerio | Structure: post-vent region Quality: curled abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Signal Transduction
- Post-translational protein modification
- Metabolism of proteins
- TNFR1-induced NFkappaB signaling pathway
- TNFR1-induced proapoptotic signaling
Biological Process
- spliceosomal tri-snRNP complex assembly
- ubiquitin-dependent protein catabolic process
- protein deubiquitination
- negative regulation of protein ubiquitination
- regulation of protein stability
Molecular Function
- thiol-dependent ubiquitin-specific protease activity
- protein binding
- adenosine receptor binding
- thiol-dependent ubiquitinyl hydrolase activity
- identical protein binding
Cellular Component
- nucleus
- cytoplasm
- lysosome
- cytosol
- plasma membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000265560
- Coding exons
- 22
- Length
- 62882
- Individuals with no LoFs
- 125624
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 124
- Defined
- 125748
- p
- 0.000493
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 1.10 | 469 | 541 | 0.867 | 0.0000290 | 6349 |
| Missense (PolyPhen) | 110 | 161.16 | 0.68253 | 1883 | ||
| Synonymous | 1.48 | 182 | 209 | 0.870 | 0.0000117 | 1807 |
| Loss of Function | 3.71 | 24 | 53.2 | 0.451 | 0.00000254 | 633 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00018 | 0.00018 | rare |
| Latino/Admixed American | 0.00027 | 0.00026 | rare |
| Ashkenazi Jewish | 0.00010 | 0.000099 | rare |
| East Asian | 0.00049 | 0.00049 | rare |
| Finnish | 0.000092 | 0.000092 | rare |
| European (Non-Finnish) | 0.00077 | 0.00076 | rare |
| South Asian | 0.00029 | 0.00029 | rare |
| Other | 0.00065 | 0.00065 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Hydrolase that deubiquitinates target proteins such as the receptor ADORA2A, PDPK1 and TRIM21. Deubiquitination of ADORA2A increases the amount of functional receptor at the cell surface. May regulate mRNA splicing through deubiquitination of the U4 spliceosomal protein PRPF3. This may prevent its recognition by the U5 component PRPF8 thereby destabilizing interactions within the U4/U6.U5 snRNP. May also play a role in the regulation of quality control in the ER. {ECO:0000269|PubMed:16316627, ECO:0000269|PubMed:16339847, ECO:0000269|PubMed:16472766, ECO:0000269|PubMed:20595234, ECO:0000269|PubMed:7784062}.;
Recessive Scores
- pRec
- 0.116
Intolerance Scores
- LoFtool
- 0.884
- RVIS EVS
- -0.82
- RVIS percentile EVS
- 12.01
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.913
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |