• 3
    Haplo
    Score
  • 0
    Triplo
    Score

Gene Facts External Data Attribution

HGNC Symbol
TCOF1 (HGNC:11654) HGNC Entrez Ensembl OMIM UCSC Uniprot GeneReviews LOVD LSDB ClinVar
HGNC Name
treacle ribosome biogenesis factor 1
Gene type
protein-coding gene
Locus type
gene with protein product
Previous symbols
No previous names found
Alias symbols
treacle, TCS
%HI
69.76(Read more about the DECIPHER Haploinsufficiency Index)
pLI
0.95(Read more about gnomAD pLI score)
LOEUF
0.31(Read more about gnomAD LOEUF score)
Cytoband
5q32-q33.1
Genomic Coordinates
GRCh37/hg19: chr5:149737260-149779856 NCBI Ensembl UCSC
GRCh38/hg38: chr5:150357697-150400293 NCBI Ensembl UCSC
MANE Select Transcript
NM_001371623.1 ENST00000643257.2 (Read more about MANE Select)
Function
Nucleolar protein that acts as a regulator of RNA polymerase I by connecting RNA polymerase I with enzymes responsible for ribosomal processing and modification (PubMed:12777385, PubMed:26399832). Required for neural crest specification: following monoubiquitination by the BCR(KBTBD8) complex, associates with NOLC1 and acts as a platform to connect RNA polymerase I with enzymes responsible for ribosomal processing and modification, leading to remodel the translational program of differentiating ... (Source: Uniprot)

Dosage Sensitivity Summary (Gene)

Dosage ID:
ISCA-24412
Curation Status:
Complete
Issue Type:
Dosage Curation - Gene
Haploinsufficiency:
Sufficient Evidence for Haploinsufficiency (3)
Triplosensitivity:
No Evidence for Triplosensitivity (0)
Last Evaluated:
04/28/2021

Haploinsufficiency (HI) Score Details

HI Score:
3
HI Evidence Strength:
Sufficient Evidence for Haploinsufficiency (Disclaimer)
HI Disease:
HI Evidence:
  • PUBMED: 9042910
    Edwards et al (1997) catalogued 25 TCOF1 variants, all but one resulting in the introduction of a premature-termination codon.
  • PUBMED: 12114482
    Splendore et al (2002) observed that the majority of pathogenic variants are small deletions and insertions causing frameshifts that are predicted to result in a truncated protein and that more than 50% of all described pathogenic variants known at the time were clustered in five exons (10, 15, 16, 23, and 24).
  • PUBMED: 15340364
    Teber et al (2004) assessed 36 patients with a clinically unequivocal diagnosis of Treacher-Collins syndrome (TCS), and detected 28 pathogenic variants, including 25 novel alterations. Most of the variants were predicted to lead to premature termination codons because of frameshift length alterations (variants in 14 patients) or nonsense substitutions (variants in six patients). Variants identified in five patients affected invariable bases at splice donor (n=2) or acceptor (n=3) sites. No variant was identified in the remaining eight patients with unequivocal diagnosis of TCS and 10 further patients, in whom the referring diagnosis of TCS was clinically doubtful.
  • PUBMED: 8875242
    Dixon et al (1996) catalogued 20 variants all resulting in the introduction of a premature stop codon in patients with a clinical diagnosis of Treacher Collins syndrome, supporting a mechanism of haploinsufficiency.
  • PUBMED: 22317976
    Bowman et al (2012) assessed 182 patients with clinical features consistent with TCS, and identified 92 pathogenic sequence level variants (57% frameshift, 23% nonsense, 16% splicing, 4% missense), as well as 5 partial gene deletions. Many of the sequence variants arose de novo.
  • PUBMED: 25790162
    Vincent et al (2016) assessed 146 patients with TCS, and identified pathogenic TCOF1 variants in 92 (63%). Of these 85/92 (92%) of them were predicted to lead to a premature stop codon as a result of frameshift variants (44 deletions, 9 duplications, 2 insertions, 3 insertions/deletions), nonsense substitutions (n = 18), and splice-site variants (n = 9). Three heterozygous missense substitutions were detected. TCOF1 variants were associated with extreme clinical variability, with no recognized phenotype–genotype correlation. Also in this TCS cohort, 9/146 (6%) had variants within POLR1D, none within POLR1C. Of those with TCS with intellectual disability, EFTUD2 variants were identified in 4/146 (3%) and 5q32 deletion encompassing TCOF1 and CAMK2A in 2/146 (1%).
HI Evidence Comments:
Phenotype (from GeneReviews): "Treacher Collins syndrome (TCS) is characterized by bilateral and symmetric downslanting palpebral fissures, malar hypoplasia, micrognathia, and external ear abnormalities. Hypoplasia of the zygomatic bones and mandible can cause significant feeding and respiratory difficulties. About 40%-50% of individuals have conductive hearing loss attributed most commonly to malformation of the ossicles and hypoplasia of the middle ear cavities. Inner ear structures tend to be normal. Other, less common abnormalities include cleft palate and unilateral or bilateral choanal stenosis or atresia. Typically intellect is normal." TSC is associated with extreme clinical variability, between families and within families. Some cases are subclinical and go undiagnosed, while others result in severe facial manifestations and airway compromise. There is no apparent genotype-phenotype correlation. It is estimated that 50-60% of TCOF1 variants occur de novo. Individuals with a TCOF1 variant have a 50% chance of passing it to their offspring. No isolated whole gene TCOF1 deletions have been reported at the time of this review. Contiguous gene deletions are reported in association with TCS phenotype plus intellectual disability. Many intragenic TCOF1 deletion and insertions have been reported.

Triplosensitivity (TS) Score Details

TS Score:
0
TS Evidence Strength:
No Evidence for Triplosensitivity (Disclaimer)
TS Evidence Comments:
No isolated whole gene TCOF1 duplications reported. No evidence for TCOF1 triplosensitivity.

Genomic View

Select assembly: (NC_000005.9) (NC_000005.10)