PAAF1

Chr 11

proteasomal ATPase associated factor 1

Also known as: PAAF, Rpn14, WDR71

NCBI Gene: 80227 ENSG00000175575 UniProt: Q9BRP4

This gene encodes a WD repeat-containing protein that regulates proteasome assembly by controlling the association between the 19S regulatory complex and the 20S core, and protects SUPT6H from proteasomal degradation. The gene is extremely intolerant to loss-of-function variants (pLI near 1.0), suggesting mutations would likely cause severe developmental disorders, though specific disease associations have not yet been established. An autosomal recessive inheritance pattern would be expected given the high constraint against heterozygous loss-of-function.

ResearchSummary from RefSeq, UniProt

This gene encodes a WD repeat-containing protein involved in regulation of association of proteasome components. During HIV infection, the encoded protein is thought to promote provirus transcription through recruitment of the 19S regulatory complex. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Jun 2012]

ResearchGenerating clinical summary…

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.21

LOEUF

Mechanism· predicted

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.21LOEUF

pLI 0.000

Z-score 0.79

OE 0.82 (0.56–1.21)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.93Z-score

OE missense 0.82 (0.73–0.93)

176 obs / 214.1 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.82 (0.56–1.21)

0≤0.351.4

Missense OE?0.82 (0.73–0.93)

0≤0.61.4

Synonymous OE?0.90

0≤1.21.6

LoF obs/exp: 18 / 22.0Missense obs/exp: 176 / 214.1Syn Z: 0.69

Background carrier burden — how many people carry a rare variant somewhere in PAAF1?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 110

546 rare PASS variants

Rare truncating (LoF)

1 in 360

139 rare PASS variants

Rare synonymous (reference)

1 in 330

200 rare PASS variants

Rare missense and truncating variants are carried at similar rates in PAAF1; 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 140	1 in 650
South Asian	~43k	1 in 75	1 in 2,900
Remaining (unassigned)	~30k	1 in 120	1 in 440
European (Finnish)	~27k	1 in 490	1 in 2,600
Admixed American	~22k	1 in 99	1 in 530
African / African American	~21k	1 in 140	1 in 420
East Asian	~20k	1 in 79	1 in 330
Ashkenazi Jewish	~13k	1 in 460	≈ 1 in 6,400
Middle Eastern	~2,884	1 in 110	≈ 1 in 1,400

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): 10 of 12 coding exons well covered in gnomAD exomes; exons 1, 4 marginal. Genomes: all 12.? see exons ↓