PCF11

Chr 11

PCF11 cleavage and polyadenylation factor subunit

NCBI Gene: 51585 ENSG00000165494 UniProt: O94913 OMIM: 608876

PCF11 encodes a component of the pre-mRNA cleavage complex II that promotes transcription termination by RNA polymerase II. Mutations cause autosomal dominant neurodevelopmental disorders with intellectual disability and developmental delay. This gene is extremely intolerant to loss-of-function variants, indicating that even small changes can have significant clinical consequences.

OMIM ResearchSummary from RefSeq, UniProt

The protein encoded by this gene binds to CLP1 to form pre-mRNA cleavage factor IIm. The encoded protein is necessary for efficient Pol II transcription termination and may be involved in degradation of the 3' product of polyA site cleavage. [provided by RefSeq, Oct 2016]

OMIM ResearchGenerating clinical summary…

Clinical highlights

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.Based on population constraint only.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.04

LOEUF· LoF intol.

LOF

Mechanism· predicted

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.04LOEUF

pLI 1.000

Z-score 8.00

OE 0.00 (0.00–0.04)

Highly constrained

Among the most LoF-intolerant genes (~top 3%)

Missense Constraint?

2.66Z-score

OE missense 0.73 (0.68–0.79)

574 obs / 783.5 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.00 (0.00–0.04)

0≤0.351.4

Missense OE?0.73 (0.68–0.79)

0≤0.61.4

Synonymous OE?1.09

0≤1.21.6

LoF obs/exp: 0 / 74.6Missense obs/exp: 574 / 783.5Syn Z: -1.21

Background carrier burden — how many people carry a rare variant somewhere in PCF11?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 46

1,811 rare PASS variants

Rare truncating (LoF)

1 in 4,400

60 rare PASS variants

Rare synonymous (reference)

1 in 54

768 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for PCF11. 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 52	1 in 4,700
South Asian	~43k	1 in 42	1 in 4,700
Remaining (unassigned)	~30k	1 in 44	≈ 1 in 9,900
European (Finnish)	~27k	1 in 150	1 in 3,000
Admixed American	~22k	1 in 37	1 in 1,200
African / African American	~21k	1 in 39	≈ 1 in 5,900
East Asian	~20k	1 in 39	≈ 1 in 20,000
Ashkenazi Jewish	~13k	1 in 180	≈ 1 in 6,300
Middle Eastern	~2,884	1 in 46	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): 7 of 16 coding exons well covered in gnomAD exomes; exons 2, 3, 7, 9, 10 and 4 more marginal. Genomes: all 16.? see exons ↓