PSMC3

protein-coding

proteasome 26S subunit, ATPase 3, the group of Proteasome|AAA ATPases

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 one of the ATPase subunits, a member of the triple-A family of ATPases that have chaperone-like activity. This subunit may compete with PSMC2 for binding to the HIV tat protein to regulate the interaction between the viral protein and the transcription complex. A pseudogene has been identified on chromosome 9. [provided by RefSeq, Jul 2008]

MANE transcript

NM_002804.5

Inheritance

AD, AR

ClinVar variants

P:12U:53B:10

Top phenotype

Deafness, cataract, impaired intellectual development, and polyneuropathy

gnomAD constraint

pLI —, LoF o/e 0.13

Max pathogenic AF

—

Genomic locus

chr11:47,418,769-47,426,473

External References & Databases

Ensembl (ENSG00000165916)

Transcript & Mutation Effects

hg38 • Region Span ~7.7 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

neurodevelopmental disorderMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0700092

Submitter: G2P

deafness, cataract, impaired intellectual development, and polyneuropathyLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0859159

Submitter: Ambry Genetics

complex neurodevelopmental disorderSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0100038

Submitter: Ambry Genetics

neurodevelopmental disorderSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0700092

Submitter: PanelApp Australia

deafness, cataract, impaired intellectual development, and polyneuropathyMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0859159

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Deafness, cataract, impaired intellectual development, and polyneuropathyAR

Manifestation: Audiologic/Otolaryngologic; Musculoskeletal; Neurologic; Ophthalmologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Comments: Cochlear implants were not described as effective

Refs: 32500975

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PSMC3 variants in ClinVar

23 Conditions Cataloged

not providedTotal: 33

Inborn genetic diseasesTotal: 26

Ebstein-Bezieau neurodevelopmental syndromeTotal: 8

Neurodevelopmental disorderTotal: 2

Deafness, cataract, impaired intellectual development, and polyneuropathyTotal: 2

PSMC3-related disordersTotal: 1

Developmental dysplasia of the hipTotal: 1

Developmental cataractTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_002804.5. 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				10 clinvar		10
missense	9 clinvar	3 clinvar	44 clinvar			56
nonsense			1 clinvar			1
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)			8 clinvar			8
Total	9	3	53	10	0	75

Highest pathogenic variant AF is 6.84046e-7

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 43 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_002804.5	RefSeq	NP_002795.2	12	MANE Select
ENST00000298852.8	Ensembl	ENSP00000298852.3	12	MANE Select
ENST00000524447.6	Ensembl	ENSP00000433596.2	10	Standard
ENST00000526993.1	Ensembl	ENSP00000435141.3	6	Standard

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

blastocyst development
viral process
protein deubiquitination
protein catabolic process
neutrophil degranulation

Molecular Function

protein binding
ATP binding
ATPase activity
proteasome-activating ATPase activity
identical protein binding

Cellular Component

proteasome complex
P-body
extracellular region
nucleus
nucleoplasm

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000298852
Coding exons: 12
Length: 7674
Individuals with no LoFs: 125743
Homozygous LoFs: 0
Heterozygous LoFs: 5
Defined: 125748
p: 0.0000199

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	3.87	85	261	0.326	0.0000149	2885
Missense (PolyPhen)		18	89.808	0.20043		939
Synonymous	0.623	97	105	0.923	0.00000634	835
Loss of Function	3.86	3	22.9	0.131	0.00000116	262

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000062	0.000062	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)	0.000035	0.000035	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

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. PSMC3 belongs to the heterohexameric ring of AAA (ATPases associated with diverse cellular activities) proteins that unfolds ubiquitinated target proteins that are concurrently translocated into a proteolytic chamber and degraded into peptides. {ECO:0000269|PubMed:1317798}.;

Recessive Scores

pRec: 0.399

Intolerance Scores

LoFtool: 0.115
RVIS EVS: -0.47
RVIS percentile EVS: 23.04

Essentials

Essential (CRISPR): E
Essential (CRISPR2): E
Essential (gene trap): E
Indispensability pred.: E
Indispensability score: 0.982

Gene Damage Prediction

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