UBTF

Chr 17AD

upstream binding transcription factor

Also known as: CONDBA, NOR-90, UBF, UBF-1, UBF1, UBF2

NCBI Gene: 7343 ENSG00000108312 UniProt: P17480 OMIM: 600673

This protein recognizes ribosomal RNA gene promoters and activates transcription by RNA polymerase I, playing a critical role in ribosome biogenesis. Mutations cause childhood-onset neurodegeneration with brain atrophy, inherited in an autosomal dominant pattern. The gene is highly constrained against loss-of-function variants (pLI ~1.0, LOEUF 0.06), indicating that even heterozygous disruption can cause severe disease.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

GOFmechanismADLOEUF 0.061 OMIM phenotype

Clinical Summary— UBTF

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Gene-Disease Validity (ClinGen)

childhood-onset motor and cognitive regression syndrome with extrapyramidal movement disorder · 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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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint

0.06LOEUF

pLI 1.000

Z-score 6.55

OE 0.00 (0.00–0.06)

Highly constrained

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

Missense Constraint

4.75Z-score

OE missense 0.38 (0.33–0.43)

172 obs / 458.0 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios

LoF OE0.00 (0.00–0.06)

0≤0.351.4

Missense OE0.38 (0.33–0.43)

0≤0.61.4

Synonymous OE1.13

0≤1.21.6

LoF obs/exp: 0 / 49.9Missense obs/exp: 172 / 458.0Syn Z: -1.42

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongUBTF-related childhood-onset neurodegenerationGOFAD

0.2199th %ile

GOF

0.3193th %ile

LOF

0.77top 5%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to loss-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOFprediction above median · LOEUF 0.06

GOF1 literature citation

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Literature Evidence

GOFOur data underscore the importance of including UBTF E210K in the differential diagnosis of neuroregression and suggest that mainly gain-of-function mechanisms contribute to the pathogenesis of the UBTF E210K neuroregression syndrome.PMID:29300972

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