CPSF1

Chr 8AD

cleavage and polyadenylation specific factor 1

Also known as: CPSF160, HSU37012, MYP27, P/cl.18

NCBI Gene: 29894 ENSG00000071894 UniProt: Q10570 OMIM: 606027

The CPSF1 protein is the largest subunit of the cleavage and polyadenylation specificity factor complex, which recognizes AAUAAA signals in pre-mRNA and facilitates RNA cleavage and poly(A) tail addition during mRNA processing. Mutations cause autosomal dominant Myopia 27, affecting eye development and retinal ganglion cell projections. The gene is highly constrained against loss-of-function variants (LOEUF 0.54), indicating that such variants are likely pathogenic.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

Cleavage and polyadenylation specificity factor (CPSF) is a multisubunit complex that plays a central role in 3-prime processing of pre-mRNAs. CPSF recognizes the AAUAAA signal in the pre-mRNA and interacts with other proteins to facilitate both RNA cleavage and poly(A) synthesis. CPSF1 is the largest subunit of the CPSF complex (Murthy and Manley, 1995 [PubMed 7590244]).[supplied by OMIM, Mar 2008]

OMIM ResearchGenerating clinical summary…

LOFmechanismADLOEUF 0.541 OMIM phenotype

Clinical Summary— CPSF1

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

8 unique Pathogenic / Likely Pathogenic· 233 VUS of 319 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.54LOEUF

pLI 0.000

Z-score 4.84

OE 0.40 (0.30–0.54)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

2.80Z-score

OE missense 0.75 (0.70–0.79)

719 obs / 963.5 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.40 (0.30–0.54)

0≤0.351.4

Missense OE?0.75 (0.70–0.79)

0≤0.61.4

Synonymous OE?1.19

0≤1.21.6

LoF obs/exp: 30 / 75.3Missense obs/exp: 719 / 963.5Syn Z: -3.05

This gene — mechanism propensity

0.5082th %ile

GOF

0.4382th %ile

LOF

0.4529th %ile

The Badonyi & Marsh model scores dominant-negative highest, but genomic evidence most strongly supports loss-of-function (haploinsufficiency) as the primary mechanism.

LOF1 literature citation · 88% of P/LP variants are LoF

Literature Evidence

LOFHere we report six rare heterozygous loss-of-function (LoF) variants in CPSF1 that were identified in six of 623 probands with eoHM but none of 2657 probands with other forms of genetic eye diseases; this difference was statistically significant (P = 4.60 Ã 10-5, Fisher's exact test).1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References

1.PMID 30689892 ↗

ClinVar Variant Classifications

319 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic5

Likely Pathogenic3

VUS233

Likely Benign19

Benign1

Conflicting3

Pathogenic

Likely Pathogenic

233

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	4	1	0	0	5
Likely Pathogenic	3	0	0	0	3
VUS	5	223	5	0	233
Likely Benign	0	3	2	14	19
Benign	0	0	0	1	1
Conflicting	—				3
Total	12	227	7	15	264

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

View in ClinVar →

56 pathogenic / likely-pathogenic (of 76) ClinVar copy-number / structural variants overlap CPSF1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →