PSMC3

Chr 11ARAD

proteasome 26S subunit, ATPase 3

Also known as: DCIDP, EBNDS, RPT5, TBP1

NCBI Gene: 5702 ENSG00000165916 UniProt: P17980 OMIM: 186852

PSMC3 encodes an ATPase subunit of the 26S proteasome that unfolds ubiquitinated proteins for degradation, maintaining cellular protein homeostasis and participating in cell cycle progression, apoptosis, and DNA damage repair. Mutations cause Ebstein-Bezieau neurodevelopmental syndrome and a syndrome characterized by deafness, cataract, impaired intellectual development, and polyneuropathy, with both autosomal recessive and autosomal dominant inheritance patterns reported. The gene is highly constrained against loss-of-function variants (pLI 0.95, LOEUF 0.34), indicating intolerance to protein-disrupting mutations.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

OMIM ResearchGenerating clinical summary…

AR/ADLOEUF 0.342 OMIM phenotypes

Clinical Summary— PSMC3

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.95). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

11 unique Pathogenic / Likely Pathogenic· 36 VUS of 77 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.34LOEUF

pLI 0.955

Z-score 3.86

OE 0.13 (0.06–0.34)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

3.87Z-score

OE missense 0.33 (0.27–0.39)

85 obs / 260.7 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.13 (0.06–0.34)

0≤0.351.4

Missense OE?0.33 (0.27–0.39)

0≤0.61.4

Synonymous OE?0.92

0≤1.21.6

LoF obs/exp: 3 / 22.9Missense obs/exp: 85 / 260.7Syn Z: 0.62

ClinVar Variant Classifications

77 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic9

Likely Pathogenic2

VUS36

Likely Benign10

Conflicting2

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	8	1	0	9
Likely Pathogenic	0	2	0	0	2
VUS	1	33	2	0	36
Likely Benign	0	0	1	9	10
Benign	0	0	0	0	0
Conflicting	—				2
Total	1	43	4	9	59

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

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16 pathogenic / likely-pathogenic (of 18) ClinVar copy-number / structural variants overlap PSMC3 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →