PUF60

Chr 8AD

poly(U) binding splicing factor 60

Also known as: FIR, RoBPI, SIAHBP1, VRJS

NCBI Gene: 22827ENSG00000179950UniProt: Q9UHX1

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]

Primary Disease Associations & Inheritance

Verheij syndromeMIM #615583
AD
335
ClinVar variants
168
Pathogenic / LP
1.00
pLI score· haploinsufficient
0
Active trials
Clinical Summary— PUF60
🧬
Gene-Disease Validity (ClinGen)
syndromic intellectual disability · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
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.
📋
ClinVar Variants
168 Pathogenic / Likely Pathogenic· 111 VUS of 335 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Dual constrained — LoF & missense intolerant
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
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?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
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?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.08 (0.03–0.24)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.32 (0.28–0.38)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.24
0≤1.21.6
LoF obs/exp: 2 / 25.7Missense obs/exp: 111 / 341.8Syn Z: -2.28

ClinVar Variant Classifications

335 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic108
Likely Pathogenic60
VUS111
Likely Benign44
Benign7
Conflicting5
108
Pathogenic
60
Likely Pathogenic
111
VUS
44
Likely Benign
7
Benign
5
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
31
3
74
0
108
Likely Pathogenic
30
18
12
0
60
VUS
5
87
18
1
111
Likely Benign
0
7
8
29
44
Benign
0
1
4
2
7
Conflicting
—5
Total6611611632335

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

View in ClinVar →

Protein Context — Lollipop Plot

PUF60 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

PUF60-related Verheij syndrome

definitive
ADLoss Of FunctionAbsent Gene Product
Dev. DisordersEye
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Verheij syndrome

MIM #615583

Molecular basis of disorder known

Autosomal dominant
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Solving the Etiology of Developmental and Epileptic Encephalopathy with Spike-Wave Activation in Sleep (D/EE-SWAS).
Viswanathan S et al.·Ann Neurol
2024
Novel PUF60 variant suggesting an interaction between Verheij and Cornelia de Lange syndrome: phenotype description and review of the literature.
Hoogenboom A et al.·Eur J Hum Genet
2024Review
[Clinical and genetic analysis of Verheij syndrome caused by PUF60 de novo mutation in a Chinese boy and literature review].
Liang Y et al.·Zhonghua Er Ke Za Zhi
2018Review
SCRIB and PUF60 are primary drivers of the multisystemic phenotypes of the 8q24.3 copy-number variant.
Dauber A et al.·Am J Hum Genet
2013
PUF60-related developmental disorder: A case series and phenotypic analysis of 10 additional patients with monoallelic PUF60 variants.
Grimes H et al.·Am J Med Genet A
2023Cohort
SNRPB promotes gastric cancer progression by regulating aberrant splicing of PUF60.
Xiang D et al.·Cell Death Dis
2025
PUF60 Promotes Chemoresistance Through Drug Efflux and Reducing Apoptosis in Gastric Cancer.
Liu Q et al.·Int J Med Sci
2025
The prevalence and clinical significance of anti-PUF60 antibodies in patients with idiopathic inflammatory myopathy.
Zhang YM et al.·Clin Rheumatol
2018Cohort
Whole Genome Sequencing of "Mutation-Negative" Individuals With Cornelia de Lange Syndrome.
Ansari M et al.·Hum Mutat
2025
PUF60 loss-of-function with normal cognition should be considered in the differential diagnosis of Klippel-Feil syndrome.
Bach MY et al.·Am J Med Genet A
2024Case report
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools