PSMA3

protein-coding

proteasome 20S subunit alpha 3, 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 peptidase T1A family, that is a 20S core alpha subunit. Two alternative transcripts encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]

MANE transcript

NM_002788.4

Inheritance

Digenic

ClinVar variants

P:1U:91B:54

Top phenotype

Proteasome-associated autoinflammatory syndrome 2

gnomAD constraint

pLI —, LoF o/e 0.06

Max pathogenic AF

—

Genomic locus

chr14:58,244,843-58,272,012

External References & Databases

Ensembl (ENSG00000100567)

Transcript & Mutation Effects

hg38 • Region Span ~27.2 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

No GenCC data available for this gene.

Clinical Genomic Database (CGD)

Proteasome-associated autoinflammatory syndrome 2Digenic

Manifestation: Allergy/Immunology/Infectious; Cardiovascular; Dermatologic; Endocrine; Gastrointestinal; Hematologic; Musculoskeletal; Neurologic

Intervention: Allergy/Immunology/Infectious

Rationale: Individuals may have recurrent infections, and awareness may allow preventative measures as well as prompt and agressive treatment of infections

Comments: Digenic inheritance has been reported

Refs: 26524591

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PSMA3 variants in ClinVar

4 Conditions Cataloged

not providedTotal: 227

not specifiedTotal: 36

PROTEASOME-ASSOCIATED AUTOINFLAMMATORY SYNDROME 1, DIGENICTotal: 2

PSMA3-related disorderTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_002788.4. 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			2 clinvar	50 clinvar	2 clinvar	54
missense			81 clinvar	2 clinvar		83
nonsense						0
start loss						0
frameshift			1 clinvar			1
splice donor/acceptor (+/-2bp)	1 clinvar		7 clinvar			8
Total	1	0	91	52	2	146

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 48 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_002788.4	RefSeq	NP_002779.1	11	MANE Select
ENST00000216455.9	Ensembl	ENSP00000216455.4	11	MANE Select
NM_152132.3	RefSeq	NP_687033.1	11	Standard
ENST00000412908.6	Ensembl	ENSP00000390491.2	11	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Proteasome - Homo sapiens (human)
Proteasome Degradation
TLR NFkB
proteasome complex
B cell receptor signaling

Biological Process

proteasomal protein catabolic process
proteasomal ubiquitin-independent protein catabolic process
viral process
protein deubiquitination
proteasome-mediated ubiquitin-dependent protein catabolic process

Molecular Function

endopeptidase activity
threonine-type endopeptidase activity
protein binding
ubiquitin protein ligase binding

Cellular Component

proteasome complex
nucleus
nucleoplasm
cytoplasm
cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000216455
Coding exons: 11
Length: 27182
Individuals with no LoFs: 125629
Homozygous LoFs: 0
Heterozygous LoFs: 3
Defined: 125632
p: 0.0000119

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.76	79	137	0.577	0.00000685	1675
Missense (PolyPhen)		8	38.595	0.20728		461
Synonymous	0.111	46	47.0	0.979	0.00000261	462
Loss of Function	3.61	1	17.1	0.0585	8.18e-7	223

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	0.000046	0.000046	rare
European (Non-Finnish)	0.000018	0.000018	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Component of the 20S core proteasome complex involved in the proteolytic degradation of most intracellular proteins. This complex plays numerous essential roles within the cell by associating with different regulatory particles. Associated with two 19S regulatory particles, forms the 26S proteasome and thus participates in the ATP-dependent degradation of ubiquitinated proteins. The 26S proteasome plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins that could impair cellular functions, and by removing proteins whose functions are no longer required. Associated with the PA200 or PA28, the 20S proteasome mediates ubiquitin-independent protein degradation. This type of proteolysis is required in several pathways including spermatogenesis (20S-PA200 complex) or generation of a subset of MHC class I-presented antigenic peptides (20S-PA28 complex). Binds to the C-terminus of CDKN1A and thereby mediates its degradation. Negatively regulates the membrane trafficking of the cell-surface thromboxane A2 receptor (TBXA2R) isoform 2. {ECO:0000269|PubMed:11350925, ECO:0000269|PubMed:14550573, ECO:0000269|PubMed:15244466, ECO:0000269|PubMed:17499743, ECO:0000269|PubMed:27176742}.;

Recessive Scores

pRec: 0.400

Intolerance Scores

RVIS EVS: -0.32
RVIS percentile EVS: 31.46

Essentials

Essential (CRISPR): E
Essential (CRISPR2): E
Essential (gene trap): E
Indispensability pred.: E
Indispensability score: 0.845

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Low	Low
Primary Immunodeficiency	Medium	Low	Medium
Cancer	Medium	Low	Medium