PSMB6

Chr 17

proteasome 20S subunit beta 6

Also known as: DELTA, LMPY

NCBI Gene: 5694 ENSG00000142507 UniProt: P28072 OMIM: 600307

PSMB6 encodes a beta subunit of the 20S proteasome core complex that degrades intracellular proteins through both ubiquitin-dependent and ubiquitin-independent pathways, displaying peptidylglutamyl-hydrolizing activity within the complex. Mutations cause autosomal recessive proteasome-associated autoinflammatory syndrome with chronic atypical neutrophilic dermatosis, characterized by early-onset recurrent fever, distinctive skin lesions, and systemic inflammation. This gene shows tolerance to loss-of-function variants in the general population, consistent with its recessive inheritance pattern.

OMIM ResearchSummary from RefSeq, UniProt

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. The encoded protein is a member of the proteasome B-type family, also known as the T1B family, and is a 20S core beta subunit in the proteasome. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Jul 2012]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.83

Clinical Summary— PSMB6

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Population Constraint (gnomAD)

Low constraint (pLI 0.02) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

31 VUS of 38 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.83LOEUF

pLI 0.016

Z-score 1.99

OE 0.40 (0.21–0.83)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.46Z-score

OE missense 0.66 (0.56–0.79)

99 obs / 149.1 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.40 (0.21–0.83)

0≤0.351.4

Missense OE?0.66 (0.56–0.79)

0≤0.61.4

Synonymous OE?1.05

0≤1.21.6

LoF obs/exp: 5 / 12.6Missense obs/exp: 99 / 149.1Syn Z: -0.26

This gene — mechanism propensity

0.75top 25%

GOF

0.6540th %ile

LOF

0.2777th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median

GOFprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

38 submitted variants in ClinVar

ClinVar

Classification Summary

VUS31

Likely Benign3

VUS

Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Total
Pathogenic	0	0
Likely Pathogenic	0	0
VUS	31	31
Likely Benign	3	3
Benign	0	0
Total	34	34

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

View in ClinVar →

23 pathogenic / likely-pathogenic (of 35) ClinVar copy-number / structural variants overlap PSMB6 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →