PSMB8
protein-codingproteasome 20S subunit beta 8, the group of Proteasome
Gene summary
The proteasome is a multicatalytic proteinase complex with a highly ordered ring-shaped 20S core structure. The core structure 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. 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 member of the proteasome B-type family, also known as the T1B family, that is a 20S core beta subunit. This gene is located in the class II region of the MHC (major histocompatibility complex). Expression of this gene is induced by gamma interferon and this gene product replaces catalytic subunit 3 (proteasome beta 5 subunit) in the immunoproteasome. Proteolytic processing is required to generate a mature subunit. Two alternative transcripts encoding two isoforms have been identified; both isoforms are processed to yield the same mature subunit. [provided by RefSeq, Jul 2008]
- LMP7
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~4.0 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0054698
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0009726
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0054698
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0009726
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0054698
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0054698
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0054698
Submitter: G2P
Clinical Genomic Database (CGD)
Manifestation: Allergy/Immunology/Infectious; Cardiovascular; Dermatologic; Endocrine; Gastrointestinal; Hematologic; Musculoskeletal; Neurologic
Intervention: Allergy/Immunology/Infectious; Cardiovascular
Rationale: Individuals may have recurrent infections, and awareness may allow preventative measures as well as prompt and agressive treatment of infections; Individuals have been described with multiple manifestations, including lethal arrhythmias, and surveillance may allow early detection and management of cardiac sequelae
Comments: Digenic inheritance has been reported
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to PSMB8 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_148919.4. 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 | 3 | 62 | 65 | |||
| missense | 3 | 2 | 109 | 13 | 127 | |
| nonsense | 4 | 3 | 3 | 10 | ||
| start loss | 0 | |||||
| frameshift | 7 | 1 | 1 | 9 | ||
| splice donor/acceptor (+/-2bp) | 2 | 1 | 3 | |||
| Total | 14 | 8 | 117 | 75 | 0 | 214 |
Highest pathogenic variant AF is 0.000024798666
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_683720.2 | 6 | MANE Select | |
| Ensembl | ENSP00000364016.4 | 6 | MANE Select | |
| RefSeq | NP_004150.1 | 6 | Standard | |
| Ensembl | ENSP00000364015.2 | 6 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Proteasome - Homo sapiens (human)
- Proteasome Degradation
- The human immune response to tuberculosis
- TLR NFkB
- antigen processing and presentation
Biological Process
- proteasomal protein catabolic process
- proteasomal ubiquitin-independent protein catabolic process
- viral process
- protein deubiquitination
- antigen processing and presentation
Molecular Function
- endopeptidase activity
- threonine-type endopeptidase activity
- protein binding
Cellular Component
- proteasome complex
- nucleus
- nucleoplasm
- cytoplasm
- cytosol
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000374882
- Coding exons
- 6
- Length
- 3987
- Individuals with no LoFs
- 125719
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 29
- Defined
- 125748
- p
- 0.000115
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.651 | 138 | 161 | 0.856 | 0.00000977 | 1772 |
| Missense (PolyPhen) | 49 | 58.802 | 0.83331 | 654 | ||
| Synonymous | -0.972 | 71 | 61.3 | 1.16 | 0.00000341 | 560 |
| Loss of Function | 2.14 | 5 | 13.5 | 0.371 | 6.78e-7 | 154 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.000067 | 0.000062 | rare |
| Latino/Admixed American | 0.000087 | 0.000087 | rare |
| Ashkenazi Jewish | 0.0011 | 0.0011 | notable |
| East Asian | 0.00011 | 0.00011 | rare |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.000091 | 0.000088 | rare |
| South Asian | 0.000066 | 0.000065 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: The proteasome is a multicatalytic proteinase complex which is characterized by its ability to cleave peptides with Arg, Phe, Tyr, Leu, and Glu adjacent to the leaving group at neutral or slightly basic pH. The proteasome has an ATP-dependent proteolytic activity. This subunit is involved in antigen processing to generate class I binding peptides. Replacement of PSMB5 by PSMB8 increases the capacity of the immunoproteasome to cleave model peptides after hydrophobic and basic residues. Acts as a major component of interferon gamma-induced sensitivity. Plays a key role in apoptosis via the degradation of the apoptotic inhibitor MCL1. May be involved in the inflammatory response pathway. In cancer cells, substitution of isoform 1 (E2) by isoform 2 (E1) results in immunoproteasome deficiency. Required for the differentiation of preadipocytes into adipocytes. {ECO:0000269|PubMed:16423992, ECO:0000269|PubMed:19443843, ECO:0000269|PubMed:21881205, ECO:0000269|PubMed:8163024}.;
- Disease
- DISEASE: Proteasome-associated autoinflammatory syndrome 1 (PRAAS1) [MIM:256040]: An autosomal recessive autoinflammatory disorder characterized by early childhood onset of recurrent fever, joint stiffness and severe contractures of the hands and feet, and erythematous skin lesions with subsequent development of lipodystrophy and laboratory evidence of immune dysregulation. Accompanying features may include muscle weakness and atrophy, hepatosplenomegaly, and microcytic anemia. {ECO:0000269|PubMed:21129723, ECO:0000269|PubMed:21852578, ECO:0000269|PubMed:21881205, ECO:0000269|PubMed:21953331, ECO:0000269|PubMed:26524591, ECO:0000269|PubMed:26567544}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Intolerance Scores
- LoFtool
- 0.856
- RVIS EVS
- 0.04
- RVIS percentile EVS
- 57.15
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.973
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |