TCOF1

protein-coding

treacle ribosome biogenesis factor 1, the group of Ribosomal biogenesis factors

Gene summary

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]

MANE transcript

NM_001371623.1

Inheritance

ClinVar variants

P:233U:425B:306

Top phenotype

Treacher Collins syndrome 1

gnomAD constraint

pLI —, LoF o/e 0.19

Max pathogenic AF

—

Genomic locus

chr5:150,357,629-150,400,308

External References & Databases

Ensembl (ENSG00000070814)

Transcript & Mutation Effects

hg38 • Region Span ~42.7 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Treacher Collins syndrome 1DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007944

Submitter: G2P

Treacher-Collins syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0002457

Submitter: ClinGen

TCOF1 was reported in relation to Treacher Collins syndrome (TCS) in 1996 (Gladwin et al., 8894686). At least 12 unique variants (nonsense, frameshift, and splicing) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data, segregation data, and experimental data. Variants in this gene have been reported in at least 13 probands in 6 publications (22317976, 29230583, 31307516, 8894686, 25790162, 30390570). Variants in this gene segregated in 9 additional family members. More evidence is available in the literature, but the maximum score for genetic evidence and experimental evidence (12 pts.) has been reached. The mechanism of disease is haploinsufficiency. This gene-disease association is supported by animal models and expression studies. In summary, TCOF1 is definitively associated with autosomal dominant Treacher Collins syndrome.

Treacher Collins syndrome 1STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007944

Submitter: Labcorp Genetics (formerly Invitae)

Treacher Collins syndrome 1STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007944

Submitter: PanelApp Australia

Treacher-Collins syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0002457

Submitter: Orphanet

Clinical Genomic Database (CGD)

Treacher Collins syndrome 1AD

Manifestation: Audiologic/Otolaryngologic; Craniofacial; Ophthalmologic

Intervention: Audiologic/Otolaryngologic

Rationale: Early recognition and treatment of hearing impairment may improve outcomes, including speech and language development

Refs: 8563749; 8875242; 8894686; 9042910; 9096354; 11013442; 14598341; 15150774; 15214011; 15340364; 19050407; 19067896; 19572402; 20301704; 22317976; 22729243; 25790162

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TCOF1 variants in ClinVar

13 Conditions Cataloged

Treacher Collins syndrome 1Total: 753

not providedTotal: 358

Inborn genetic diseasesTotal: 244

TCOF1-related disorderTotal: 94

not specifiedTotal: 43

Treacher Collins syndromeTotal: 9

Hearing impairmentTotal: 2

Cleft lip/palateTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001371623.1. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			6 clinvar	160 clinvar	21 clinvar	187
missense	3 clinvar	9 clinvar	402 clinvar	113 clinvar	12 clinvar	539
nonsense	32 clinvar	11 clinvar				43
start loss	3 clinvar					3
frameshift	111 clinvar	45 clinvar	4 clinvar			160
splice donor/acceptor (+/-2bp)	12 clinvar	7 clinvar	13 clinvar			32
Total	161	72	425	273	33	964

Highest pathogenic variant AF is 0.0000065708205

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 176 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001371623.1	RefSeq	NP_001358552.1	26	MANE Select
ENST00000643257.2	Ensembl	ENSP00000493815.1	26	MANE Select
NM_000356.4	RefSeq	NP_000347.2	25	Standard
NM_001008657.3	RefSeq	NP_001008657.1	18	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Ribosome biogenesis in eukaryotes - Homo sapiens (human)

Biological Process

skeletal system development
regulation of translation
neural crest formation
neural crest cell development

Molecular Function

RNA polymerase I core binding
RNA binding
transporter activity
protein binding
protein heterodimerization activity

Cellular Component

fibrillar center
nucleus
nucleolus
cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000504761
Coding exons: 26
Length: 42670
Individuals with no LoFs: 125720
Homozygous LoFs: 0
Heterozygous LoFs: 28
Defined: 125748
p: 0.000111

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.339	773	800	0.966	0.0000438	9467
Missense (PolyPhen)		196	226.22	0.86643		3025
Synonymous	-1.24	365	336	1.09	0.0000213	3123
Loss of Function	5.92	12	62.6	0.192	0.00000302	843

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00019	0.00018	rare
Latino/Admixed American	0.000029	0.000029	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.00017	0.00017	rare
South Asian	0.000098	0.000098	rare
Other	0.00033	0.00033	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: 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 cells in favor of neural crest specification (PubMed:26399832). {ECO:0000269|PubMed:12777385, ECO:0000269|PubMed:26399832}.;
Disease: DISEASE: Treacher Collins syndrome 1 (TCS1) [MIM:154500]: A form of Treacher Collins syndrome, a disorder of craniofacial development. Treacher Collins syndrome is characterized by a combination of bilateral downward slanting of the palpebral fissures, colobomas of the lower eyelids with a paucity of eyelashes medial to the defect, hypoplasia of the facial bones, cleft palate, malformation of the external ears, atresia of the external auditory canals, and bilateral conductive hearing loss. {ECO:0000269|PubMed:9042910}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.195

Intolerance Scores

LoFtool: 0.456
RVIS EVS: 0.47
RVIS percentile EVS: 78.7

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): E
Indispensability pred.: E
Indispensability score: 0.575

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	High
Cancer	Medium	Medium	Medium