TCOF1

Chr 5AD

treacle ribosome biogenesis factor 1

Also known as: MFD1, TCS, TCS1, treacle

NCBI Gene: 6949ENSG00000070814UniProt: Q13428OMIM: 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.

GeneReviewsOMIMResearchSummary from RefSeq, OMIM, UniProt
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
98 unique Pathogenic / Likely Pathogenic· 247 VUS of 584 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 OE0.19 (0.12–0.31)
0≤0.351.4
Missense OE0.97 (0.91–1.02)
0≤0.61.4
Synonymous OE1.09
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
DN
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 · 86% of P/LP variants are LoF · LOEUF 0.31

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.PMID:15214011

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

ClinVar Variant Classifications

584 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic68
Likely Pathogenic30
VUS247
Likely Benign164
Benign29
Conflicting16
68
Pathogenic
30
Likely Pathogenic
247
VUS
164
Likely Benign
29
Benign
16
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
56
3
9
0
68
Likely Pathogenic
28
1
1
0
30
VUS
1
228
15
3
247
Likely Benign
0
30
48
86
164
Benign
0
11
6
12
29
Conflicting
—16
Total8527379101554

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

View in ClinVar →

Protein Context — Lollipop Plot

TCOF1 · protein map & ClinVar variants

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

3D Protein StructureAlphaFold

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →
Clinical Literature
Open Research Assistant →
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Top 5 full-text resultsSearch PubTator3 ↗
Key Publications
Landmark & review papers · by relevance
PubMed
Top 5 results · since 2015Search PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients