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

This gene encodes a member of the HMG-box DNA-binding protein family. The encoded protein plays a critical role in ribosomal RNA transcription as a key component of the pre-initiation complex, mediating the recruitment of RNA polymerase I to rDNA promoter regions. The encoded protein may also play important roles in chromatin remodeling and pre-rRNA processing, and its activity is regulated by both phosphorylation and acetylation. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. Pseudogenes of this gene are located on the short arm of chromosomes 3, 11 and X and the long arm of chromosome 11. [provided by RefSeq, Aug 2011]

OMIM ResearchGenerating clinical summary…

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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ClinVar Variants

7 unique Pathogenic / Likely Pathogenic· 110 VUS of 198 total submissions

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

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?

0.06LOEUF

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 OE?0.00 (0.00–0.06)

0≤0.351.4

Missense OE?0.38 (0.33–0.43)

0≤0.61.4

Synonymous OE?1.13

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

This gene — mechanism propensity

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 · 71% of P/LP variants are LoF · 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.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 29300972 ↗

ClinVar Variant Classifications

198 submitted variants in ClinVar

ClinVar

Classification Summary

Likely Pathogenic7

VUS110

Likely Benign25

Benign22

Conflicting1

Likely Pathogenic

110

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	0	0
Likely Pathogenic	5	2	0	0	7
VUS	13	93	3	1	110
Likely Benign	0	3	11	11	25
Benign	0	1	15	6	22
Conflicting	—				1
Total	18	99	29	18	165

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

View in ClinVar →

9 pathogenic / likely-pathogenic (of 11) ClinVar copy-number / structural variants overlap UBTF — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →