TCOF1

Chr 5AD

treacle ribosome biogenesis factor 1

Also known as: MFD1, TCS, TCS1, treacle

NCBI Gene: 6949 ENSG00000070814 UniProt: Q13428 OMIM: 606847

TCOF1 encodes treacle, a nucleolar protein that regulates RNA polymerase I and is required for neural crest specification through its role in ribosomal processing and modification. Mutations cause Treacher Collins syndrome 1, characterized by abnormal craniofacial development, with autosomal dominant inheritance. The gene is highly constrained against loss-of-function variants (pLI 0.95), reflecting its essential role in early development.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a nucleolar protein with a LIS1 homology domain. The protein is involved in ribosomal DNA gene transcription through its interaction with upstream binding factor (UBF). Mutations in this gene have been associated with Treacher Collins syndrome, a disorder which includes abnormal craniofacial development. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2008]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismADLOEUF 0.311 OMIM phenotype

Clinical Summary— TCOF1

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Gene-Disease Validity (ClinGen)

Treacher-Collins syndrome · 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 0.95). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

234 unique Pathogenic / Likely Pathogenic· 440 VUS of 1171 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — TCOF1

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.31LOEUF

pLI 0.954

Z-score 5.92

OE 0.19 (0.12–0.31)

Highly constrained

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

Missense Constraint?

0.34Z-score

OE missense 0.97 (0.91–1.02)

773 obs / 800.0 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.19 (0.12–0.31)

0≤0.351.4

Missense OE?0.97 (0.91–1.02)

0≤0.61.4

Synonymous OE?1.09

0≤1.21.6

LoF obs/exp: 12 / 62.6Missense obs/exp: 773 / 800.0Syn Z: -1.24

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveTCOF1-related Treacher Collins syndromeLOFAD

This gene — mechanism propensity

0.2499th %ile

GOF

0.1699th %ile

LOF

0.73top 10%

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

LOFprediction above median · 1 literature citation · 91% of P/LP variants are LoF · LOEUF 0.31 · ClinGen HI: Sufficient evidence for dosage pathogenicity

Literature Evidence

LOFTreacher Collins syndrome (TCS) is caused by mutations in TCOF1 of the nonsense, small deletion, and small insertion types, which most likely result in haploinsufficiency.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 15214011 ↗

ClinVar Variant Classifications

1171 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic163

Likely Pathogenic71

VUS440

Likely Benign331

Benign79

Conflicting55

163

Pathogenic

Likely Pathogenic

440

VUS

331

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	153	4	6	0	163
Likely Pathogenic	61	6	4	0	71
VUS	4	410	22	4	440
Likely Benign	0	68	105	158	331
Benign	0	18	37	24	79
Conflicting	—				55
Total	218	506	174	186	1,139

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

View in ClinVar →

13 pathogenic / likely-pathogenic (of 15) ClinVar copy-number / structural variants overlap TCOF1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →