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…

Primary Disease Associations & Inheritance

Verheij syndromeMIM #615583

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · syndromic intellectual disability · AD · ClinGen 2021

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype) and the gene is intolerant of it in the population — truncating, frameshift and canonical splice variants carry more prior weight here than missense.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.24

LOEUF· LoF intol.

LOF

Mechanism· G2P

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

Background carrier burden — how many people carry a rare variant somewhere in PUF60?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 170

494 rare PASS variants

Rare truncating (LoF)

1 in 3,300

45 rare PASS variants

Rare synonymous (reference)

1 in 79

416 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for PUF60. 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 220	1 in 2,800
South Asian	~43k	1 in 160	≈ 1 in 14,000
Remaining (unassigned)	~30k	1 in 130	≈ 1 in 30,000
European (Finnish)	~27k	1 in 570	1 in 3,600
Admixed American	~22k	1 in 200	≈ 1 in 4,600
African / African American	~21k	1 in 140	1 in 680
East Asian	~20k	1 in 270	1 in 4,000
Ashkenazi Jewish	~13k	1 in 390	≈ 1 in 13,000
Middle Eastern	~2,884	1 in 140	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): 11 of 12 coding exons well covered in gnomAD exomes; exon 1 marginal. Genomes: all 12.? see exons ↓