PUF60

Chr 8AD

poly(U) binding splicing factor 60

Also known as: FIR, RoBPI, SIAHBP1, VRJS

NCBI Gene: 22827 ENSG00000179950 UniProt: Q9UHX1 OMIM: 604819

The protein encoded by this gene is a DNA- and RNA-binding protein that regulates pre-mRNA splicing, transcription (including MYC repression), and apoptosis. Mutations cause Verheij syndrome, inherited in an autosomal dominant pattern. This gene is highly constrained against loss-of-function variants (pLI 0.997, LOEUF 0.245), indicating that such mutations are likely to have significant clinical consequences.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a nucleic acid-binding protein that plays a role in a variety of nuclear processes, including pre-mRNA splicing and transcriptional regulation. The encoded protein forms a complex with the far upstream DNA element (FUSE) and FUSE-binding protein at the myelocytomatosis oncogene (MYC) promoter. This complex represses MYC transcription through the core-TFIIH basal transcription factor. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Aug 2012]

OMIM ResearchGenerating clinical summary…

LOFmechanismADLOEUF 0.241 OMIM phenotype

Clinical Summary— PUF60

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Gene-Disease Validity (ClinGen)

syndromic intellectual disability · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

109 unique Pathogenic / Likely Pathogenic· 111 VUS of 296 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.24LOEUF

pLI 0.997

Z-score 4.33

OE 0.08 (0.03–0.24)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

4.44Z-score

OE missense 0.32 (0.28–0.38)

111 obs / 341.8 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.08 (0.03–0.24)

0≤0.351.4

Missense OE?0.32 (0.28–0.38)

0≤0.61.4

Synonymous OE?1.24

0≤1.21.6

LoF obs/exp: 2 / 25.7Missense obs/exp: 111 / 341.8Syn Z: -2.28

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitivePUF60-related Verheij syndromeLOFAD

This gene — mechanism propensity

0.3296th %ile

GOF

0.4480th %ile

LOF

0.78top 5%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · 1 literature citation · 80% of P/LP variants are LoF · LOEUF 0.24 · ClinGen HI: Sufficient evidence for dosage pathogenicity

Literature Evidence

LOFThe distribution of the heterozygous de novo variants (DNV) is shown in context of the genomic structure of PUF60 in Figure 1. Nine of the DNV were predicted to cause loss-of function suggesting haploinsufficiency as the likely mutational mechanism.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 28327570 ↗

ClinVar Variant Classifications

296 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic52

Likely Pathogenic57

VUS111

Likely Benign45

Benign6

Conflicting6

Pathogenic

Likely Pathogenic

111

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	49	3	0	0	52
Likely Pathogenic	38	19	0	0	57
VUS	8	94	8	1	111
Likely Benign	0	10	6	29	45
Benign	0	0	4	2	6
Conflicting	—				6
Total	95	126	18	32	277

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

View in ClinVar →

65 pathogenic / likely-pathogenic (of 71) ClinVar copy-number / structural variants overlap PUF60 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →