PSMD12
protein-codingproteasome 26S subunit, non-ATPase 12, the group of Proteasome
Gene summary
The 26S proteasome is a multicatalytic proteinase complex with a highly ordered structure composed of 2 complexes, a 20S core and a 19S regulator. The 20S core is composed of 4 rings of 28 non-identical subunits; 2 rings are composed of 7 alpha subunits and 2 rings are composed of 7 beta subunits. The 19S regulator is composed of a base, which contains 6 ATPase subunits and 2 non-ATPase subunits, and a lid, which contains up to 10 non-ATPase subunits. Proteasomes are distributed throughout eukaryotic cells at a high concentration and cleave peptides in an ATP/ubiquitin-dependent process in a non-lysosomal pathway. An essential function of a modified proteasome, the immunoproteasome, is the processing of class I MHC peptides. This gene encodes a non-ATPase subunit of the 19S regulator. A pseudogene has been identified on chromosome 3. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2015]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~28.7 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0054591
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0054591
Submitter: ClinGen
*PSMD12* was first reported in relation to autosomal dominant Stankiewicz-Isidor Syndrome (STISS) in 2017 (Kury et al. 2017, PMID: 28132691). STISS is a neurodevelopmental disorder characterized by delayed psychomotor development, intellectual disability, behavioral issues, mild craniofacial anomalies and variable congenital defects. Ten variants (8 nonsense and 2 splice site) that have been reported in 10 probands in 3 publications (PMIDs: 28132691, 30421579, 34906456) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity appears to be loss-of-function. This gene-disease relationship is also supported by an animal model (PMIDs: 28132691). A *PSMD12* zebrafish CRISPR/Cas9 knockout model exhibited microcephaly, decreased convolution of the renal tubules, and abnormal craniofacial morphology consistent with phenotypes in individuals with STISS (PMIDs: 28132691). In summary, there is definitive evidence supporting the relationship between *PSMD12* and autosomal dominant Stankiewicz-Isidor Syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Intellectual Disability and Autism GCEP on March 5, 2024 (SOP Version 10).
Inheritance Pattern: AD
Disease ID:MONDO:0054591
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0000508
Submitter: Orphanet
Clinical Genomic Database (CGD)
Manifestation: Cardiovascular; Craniofacial; Genitourinary; Musculoskeletal; Neurologic; Ophthalmologic
Intervention: Cardiovascular
Rationale: The condition can involve congenital cardiac anomalies, and awareness may allow early management
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to PSMD12 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_002816.5. 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 | 6 | 2 | 9 | ||
| missense | 113 | 5 | 1 | 119 | ||
| nonsense | 12 | 8 | 3 | 23 | ||
| start loss | 1 | 1 | ||||
| frameshift | 7 | 6 | 1 | 14 | ||
| splice donor/acceptor (+/-2bp) | 2 | 2 | 6 | 10 | ||
| Total | 21 | 16 | 125 | 11 | 3 | 176 |
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_002807.1 | 11 | MANE Select | |
| Ensembl | ENSP00000348442.3 | 11 | MANE Select | |
| RefSeq | NP_001303270.1 | 9 | Standard | |
| RefSeq | NP_777360.1 | 10 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| psmd12 | Danio rerio | Structure: pronephric proximal convoluted tubule Quality: decreased size abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Epstein-Barr virus infection - Homo sapiens (human)
- Proteasome - Homo sapiens (human)
- Proteasome Degradation
- Parkin-Ubiquitin Proteasomal System pathway
- TLR NFkB
Biological Process
- protein deubiquitination
- proteasome-mediated ubiquitin-dependent protein catabolic process
- neutrophil degranulation
- post-translational protein modification
Cellular Component
- proteasome complex
- extracellular region
- nucleoplasm
- cytoplasm
- cytosol
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000356126
- Coding exons
- 11
- Length
- 28712
- Individuals with no LoFs
- 125623
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 1
- Defined
- 125624
- p
- 0.00000398
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 1.87 | 163 | 246 | 0.664 | 0.0000124 | 2992 |
| Missense (PolyPhen) | 27 | 60.347 | 0.44741 | 770 | ||
| Synonymous | 1.70 | 67 | 87.1 | 0.769 | 0.00000447 | 825 |
| Loss of Function | 4.85 | 1 | 29.3 | 0.0341 | 0.00000172 | 341 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| 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) | 0.0000088 | 0.0000088 | rare |
| South Asian | 0 | 0.0 | absent |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required. Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair. {ECO:0000269|PubMed:1317798}.;
- Disease
- DISEASE: Stankiewicz-Isidor syndrome (STISS) [MIM:617516]: A neurodevelopmental disorder characterized by delayed psychomotor development, intellectual disability, behavioral disorders, mild dysmorphism, ophthalmologic anomalies, feeding difficulties, deafness, and variable congenital malformations of the cardiac and/or urogenital systems. {ECO:0000269|PubMed:28132691}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.156
Intolerance Scores
- LoFtool
- 0.157
- RVIS EVS
- -0.32
- RVIS percentile EVS
- 31.69
Essentials
- Essential (CRISPR)
- E
- Essential (CRISPR2)
- E
- Essential (gene trap)
- E
- Indispensability pred.
- E
- Indispensability score
- 0.885
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |