USP46
protein-codingubiquitin specific peptidase 46, the group of Ubiquitin specific peptidases
Gene summary
Modification of cellular proteins by ubiquitin is an essential regulatory mechanism controlled by the coordinated action of multiple ubiquitin-conjugating and deubiquitinating enzymes. USP46 belongs to a large family of cysteine proteases that function as deubiquitinating enzymes (Quesada et al., 2004 [PubMed 14715245]).[supplied by OMIM, Jun 2009]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~68.3 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 USP46 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_022832.4. 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 | 2 | 3 | |||
| missense | 20 | 20 | ||||
| nonsense | 0 | |||||
| start loss | 0 | |||||
| frameshift | 0 | |||||
| splice donor/acceptor (+/-2bp) | 5 | 5 | ||||
| Total | 0 | 0 | 25 | 1 | 2 | 28 |
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_073743.2 | 9 | MANE Select | |
| Ensembl | ENSP00000407818.2 | 9 | MANE Select | |
| RefSeq | NP_001127695.1 | 9 | Standard | |
| RefSeq | NP_001273696.1 | 9 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Circadian Clock
- Mitochondrial biogenesis
- NR1D1 (REV-ERBA) represses gene expression
- Circadian Clock
Biological Process
- behavioral fear response
- ubiquitin-dependent protein catabolic process
- adult feeding behavior
- protein deubiquitination
- regulation of synaptic transmission, GABAergic
Molecular Function
- cysteine-type endopeptidase activity
- thiol-dependent ubiquitin-specific protease activity
- protein binding
- thiol-dependent ubiquitinyl hydrolase activity
- metal ion binding
Cellular Component
- glutamatergic synapse
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000441222
- Coding exons
- 9
- Length
- 68365
- Individuals with no LoFs
- 124698
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 5
- Defined
- 124703
- p
- 0.0000200
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 2.87 | 85 | 199 | 0.428 | 0.0000109 | 2437 |
| Missense (PolyPhen) | 10 | 50.175 | 0.1993 | 678 | ||
| Synonymous | 1.75 | 55 | 74.1 | 0.742 | 0.00000416 | 630 |
| Loss of Function | 3.32 | 3 | 18.3 | 0.164 | 8.41e-7 | 241 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00013 | 0.00013 | rare |
| Latino/Admixed American | 0 | 0.0 | absent |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.000027 | 0.000027 | rare |
| South Asian | 0 | 0.0 | absent |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Deubiquitinating enzyme that plays a role in behavior, possibly by regulating GABA action. May act by mediating the deubiquitination of GAD1/GAD67 (By similarity). Has almost no deubiquitinating activity by itself and requires the interaction with WDR48 to have a high activity (PubMed:19075014, PubMed:26388029). Not involved in deubiquitination of monoubiquitinated FANCD2 (PubMed:19075014). {ECO:0000250|UniProtKB:P62069, ECO:0000269|PubMed:19075014, ECO:0000269|PubMed:26388029}.;
Recessive Scores
- pRec
- 0.118
Intolerance Scores
- RVIS EVS
- -0.23
- RVIS percentile EVS
- 36.86
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.782
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |