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…

Primary Disease Associations & Inheritance

?Deafness, cataract, impaired intellectual development, and polyneuropathyMIM #619354

Ebstein-Bezieau neurodevelopmental syndromeMIM #621539

Clinical highlights

Gene–disease validity

Not independently assessedOMIM lists Ebstein-Bezieau neurodevelopmental syndrome; no ClinGen or GenCC tier

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.34

LOEUF· LoF intol.

—

Mechanism

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

Background carrier burden — how many people carry a rare variant somewhere in PSMC3?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 700

292 rare PASS variants

Rare truncating (LoF)

1 in 1,400

54 rare PASS variants

Rare synonymous (reference)

1 in 250

247 rare PASS variants

Rare missense and truncating variants are carried at similar rates in PSMC3; this gene does not show strong loss-of-function constraint by this measure. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 770	1 in 1,200
South Asian	~43k	1 in 650	1 in 4,900
Remaining (unassigned)	~30k	1 in 740	1 in 2,100
European (Finnish)	~27k	1 in 440	≈ 1 in 8,400
Admixed American	~22k	1 in 400	1 in 3,000
African / African American	~21k	1 in 360	1 in 1,800
East Asian	~20k	1 in 710	1 in 1,100
Ashkenazi Jewish	~13k	1 in 1,000	≈ 1 in 4,200
Middle Eastern	~2,884	≈ 1 in 720	none seen

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): All 12 coding exons well covered in gnomAD exomes and genomes.? see exons ↓