TCOF1

Summary

TCOF1 (treacle ribosome biogenesis factor 1, HGNC:11654) is a protein-coding gene on chromosome 5q32-q33.1, encoding Treacle protein (Q13428). Nucleolar protein that acts as a regulator of RNA polymerase I by connecting RNA polymerase I with enzymes responsible for ribosomal processing and modification. It is a selective cancer dependency (DepMap: 55.0% of cell lines) and haploinsufficient (ClinGen: sufficient evidence).

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.

Source: NCBI Gene 6949 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Treacher-Collins syndrome (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 2
• Clinical variants (ClinVar): 1,137 total — 160 pathogenic, 59 likely-pathogenic
• Phenotypes (HPO): 87
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• Cancer dependency (DepMap): dependent in 55.0% of screened cell lines
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• MANE Select transcript: NM_001371623

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11654
Approved symbol	TCOF1
Name	treacle ribosome biogenesis factor 1
Location	5q32-q33.1
Locus type	gene with protein product
Status	Approved
Aliases	treacle, TCS
Ensembl gene	ENSG00000070814
Ensembl biotype	protein_coding
OMIM	606847
Entrez	6949

Gene structure

Transcript identifiers

Ensembl transcripts: 67 — 61 protein_coding, 3 retained_intron, 2 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000323668, ENST00000377797, ENST00000394269, ENST00000427724, ENST00000439160, ENST00000445265, ENST00000504761, ENST00000506063, ENST00000506630, ENST00000506767, ENST00000513346, ENST00000513538, ENST00000514442, ENST00000515035, ENST00000515516, ENST00000643257, ENST00000643812, ENST00000646961, ENST00000650162, ENST00000674413, ENST00000930540, ENST00000930541, ENST00000930542, ENST00000930543, ENST00000930544, ENST00000930545, ENST00000930546, ENST00000930547, ENST00000930548, ENST00000930549, ENST00000930550, ENST00000930551, ENST00000930552, ENST00000930553, ENST00000930554, ENST00000930555, ENST00000930556, ENST00000930557, ENST00000930558, ENST00000930559, ENST00000930560, ENST00000930561, ENST00000930562, ENST00000930563, ENST00000930564, ENST00000930565, ENST00000930566, ENST00000930567, ENST00000930568, ENST00000930569, ENST00000930570, ENST00000930571, ENST00000930572, ENST00000930573, ENST00000930574, ENST00000930575, ENST00000930576, ENST00000930577, ENST00000930578, ENST00000930579, ENST00000930580, ENST00000930581, ENST00000930582, ENST00000930583, ENST00000930584, ENST00000930585, ENST00000930586

RefSeq mRNA: 7 — MANE Select: NM_001371623 NM_000356, NM_001008657, NM_001135243, NM_001135244, NM_001135245, NM_001195141, NM_001371623

CCDS: CCDS4306, CCDS43388, CCDS47305, CCDS47306, CCDS47307, CCDS54936, CCDS93805

Canonical transcript exons

ENST00000643257 — 27 exons

Exon	Start	End
ENSE00000972857	150374617	150374811
ENSE00001171398	150367844	150367917
ENSE00001198833	150368716	150368902
ENSE00001198956	150364113	150364252
ENSE00001198964	150361156	150361211
ENSE00001606922	150392705	150392790
ENSE00002204952	150398354	150398451
ENSE00002210082	150391544	150391657
ENSE00002223579	150391957	150392176
ENSE00002236001	150396282	150396842
ENSE00002300958	150393372	150393552
ENSE00002322879	150399022	150399070
ENSE00003507108	150376423	150376620
ENSE00003516904	150379229	150379408
ENSE00003535247	150374954	150375163
ENSE00003551581	150387902	150388088
ENSE00003573644	150372006	150372236
ENSE00003580151	150375721	150375909
ENSE00003594011	150378905	150379042
ENSE00003596631	150374174	150374386
ENSE00003611163	150376082	150376330
ENSE00003616935	150369529	150369602
ENSE00003642419	150379532	150379732
ENSE00003647292	150375339	150375554
ENSE00003648859	150389887	150390023
ENSE00003818116	150399810	150400293
ENSE00003897764	150357697	150357854

Expression profiles

Bgee: expression breadth ubiquitous, 265 present calls, max score 97.44.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 16.3216 / max 110.6306, expressed in 1775 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
59422	16.3216	1775

Top tissues by expression

288 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
sural nerve	UBERON:0015488	97.44	gold quality
oocyte	CL:0000023	91.14	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	88.15	gold quality
granulocyte	CL:0000094	87.72	gold quality
pericardium	UBERON:0002407	87.66	gold quality
lymph node	UBERON:0000029	87.21	gold quality
pylorus	UBERON:0001166	87.15	gold quality
lower esophagus muscularis layer	UBERON:0035833	86.72	gold quality
lower esophagus	UBERON:0013473	86.71	gold quality
apex of heart	UBERON:0002098	86.53	gold quality
tendon of biceps brachii	UBERON:0008188	86.39	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	86.36	gold quality
gastrocnemius	UBERON:0001388	86.33	gold quality
stromal cell of endometrium	CL:0002255	86.32	gold quality
muscle layer of sigmoid colon	UBERON:0035805	86.24	gold quality
ventricular zone	UBERON:0003053	86.22	gold quality
parotid gland	UBERON:0001831	86.04	silver quality
muscle of leg	UBERON:0001383	85.97	gold quality
popliteal artery	UBERON:0002250	85.90	gold quality
vena cava	UBERON:0004087	85.88	silver quality
tibial artery	UBERON:0007610	85.88	gold quality
calcaneal tendon	UBERON:0003701	85.81	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	85.72	gold quality
body of tongue	UBERON:0011876	85.68	gold quality
hindlimb stylopod muscle	UBERON:0004252	85.56	gold quality
pharyngeal mucosa	UBERON:0000355	85.55	gold quality
bone marrow cell	CL:0002092	85.54	gold quality
cortical plate	UBERON:0005343	85.49	gold quality
superior surface of tongue	UBERON:0007371	85.48	gold quality
nipple	UBERON:0002030	85.43	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-HCAD-4	yes	954.42
E-ANND-3	yes	5.23
E-MTAB-9689	no	203.95

Regulation

Is transcription factor: no

Functional genomics

ClinGen dosage: haploinsufficiency 3 (sufficient evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map DepMap (CRISPR cell-line fitness): dependent in 55.0% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 40)

• The identification of a novel pathogenic missense change in exon 2 of the TCOF1 gene suggests that a functionally important domain of treacle exists near the N-terminus. (PMID:12114482)
• Patients with Goldenhar, Nager, or Miller syndromes may resemble Treacher-Collins, but are unlikely to have mutations at this locus. (PMID:12210332)
• Identification of 231-nucleotide(nt) exon 6A and 108-nt exon 16A and isoforms with exon 6A are up to 3.7-fold more abundant than alternatively spliced variants without exon 6A, but only minor isoforms contain exon 16A. (PMID:15019983)
• In this study we identified a TCOF1 1408delAG heterozygous mutation in a patient with the clinical diagnosis of TCS (treacher collins syndrome). (PMID:15039977)
• Results show that treacle is involved in ribosomal DNA gene transcription by interacting with upstream binding factor (UBF). (PMID:15249688)
• A novel mutation within exon 6A is associated with Treacher Collins syndrome. (PMID:15832313)
• The -346T allele impairs DNA-binding to the YY1 transcription factor, and this promoter variant represents a candidate allele to explain the clinical variability in patients bearing Treacher Collins syndrome. (PMID:16102917)
• A 5-bp deletion in exon 22 of the TCOF1 gene (3469del ACTCT) was found to cause a premature stop codon. (PMID:16801042)
• These observations strongly suggest that the TCOF1 genetic changes observed in these five patients might be related to oculo-auriculo-vertebral spectrum symptoms. (PMID:17786119)
• TCOF1 may influence risk of cleft palate through maternal transmission. (PMID:18688869)
• It has been hypothesized that mutations in Tcof1 disrupt ribosome biogenesis to a degree that is insufficient to meet the proliferative needs of the neuroepithelium and neural crest cells. (PMID:19027870)
• The novel mutation of Ala26Val is considered to affect the LisH domain, an important domain of treacle. All of the mutations thus far detected in exon 5 have resulted in frameshift, but a nonsense mutation was detected (Lys159Stop). (PMID:19067896)
• central repeated domain of treacle binds with RNA polymerase I, while that the treacle C-terminus is involved in rDNA promoter recognition and UBF recruitment. (PMID:19527688)
• We demonstrated that adult leucocytes and mesenchymal cells from TCS patients present significantly reduced levels of TCOF1 (PMID:20003452)
• 6 of 12 patients diagnosed with hemifacial microsomia exhibited a novel frameshift mutation c. 4127 ins G in exon 24 in the TCOF1 gene. (PMID:21848650)
• Fifteen mutations were reported, including twelve novel and three already described in 14 sporadic patients and in 3 familial cases of Treacher Collins syndrome. (PMID:21951868)
• Gene rearrangements in TCOF1 are responsible for Treacher-Collins-Franceschetti syndrome. (PMID:22317976)
• Presents the case of a male with Treacher Collins syndrome with a heterozygous de novo frameshift mutation within the TCOF1 gene (c.790_791delAG,p.Ser264GlnfsX7), as well as findings from three other individuals from two families with the same mutation. (PMID:22729243)
• we describe for the first time, two patients with MFD and ID and for whom a deletion encompassing TCOF1 and CAMK2A has been identified (PMID:23695276)
• TCOF1 genetic mutation can be a cause of Treacher Collins syndrome in Chinese patients. (PMID:23838542)
• Autosomal recessive POLR1D mutation with decrease of TCOF1 mRNA is responsible for Treacher Collins syndrome. (PMID:24603435)
• Mutations in TCOF1, POLR1C and POLR1D have all been implicated in causing TCS (PMID:24690222)
• Treacle-mediated NBS1 recruitment into the nucleoli regulates rRNA silencing in trans in the presence of distant chromosome breaks. (PMID:25064736)
• findings identify TCOF1 as a DDR factor that could cooperate with ATM and NBS1 to suppress inappropriate rDNA transcription and maintain genomic integrity after DNA damage. (PMID:25512513)
• We report a clinical and extensive molecular study, including TCOF1, POLR1D, POLR1C, and EFTUD2 genes, in a series of 146 patients with TCS. (PMID:25790162)
• The analysis results showed that the Tcof1-related genes were enriched in various biological processes, including cell proliferation, apoptosis, cell cycle, differentiation, and migration. (PMID:27300466)
• Performed mutational analysis of TCOF1, GSC, and HOXA2 to determine the mutational features of the 3 genes in Chinese patients with Treacher Collins syndrome. (PMID:27526242)
• Data indicate that Treacher Collins-Franceschetti syndrome 1 protein (TCOF1) was the main disease-causing gene for the Chinese Treacher Collins syndrome (TCS) population and its mutation spectrum. (PMID:29230583)
• Acinar Progenitor Cell Model Identifies Treacle-Dependent Radioresistance (PMID:31141469)
• POLR1B and neural crest cell anomalies in Treacher Collins syndrome type 4. (PMID:31649276)
• TOPBP1 recruitment is mediated by phosphorylation-dependent interactions between three of its BRCT domains and conserved phosphorylated Ser/Thr residues at the C-terminus of the nucleolar phosphoprotein Treacle. (PMID:31913317)
• Treacher Collins syndrome: A novel TCOF1 mutation and monopodial stapes. (PMID:32351010)
• TRF2 recruits nucleolar protein TCOF1 to coordinate telomere transcription and replication. (PMID:33082515)
• De novo TCOF1 mutation in Treacher Collins syndrome. (PMID:34058530)
• Treacle and TOPBP1 control replication stress response in the nucleolus. (PMID:34100862)
• TCOF1 upregulation in triple-negative breast cancer promotes stemness and tumour growth and correlates with poor prognosis. (PMID:34718356)
• TCOF1 coordinates oncogenic activation and rRNA production and promotes tumorigenesis in HCC. (PMID:34904330)
• The oncogenic role of treacle ribosome biogenesis factor 1 (TCOF1) in human tumors: a pan-cancer analysis. (PMID:35093935)
• Genetic mutations in ribosomal biogenesis gene TCOF1 identified in human neural tube defects. (PMID:36808708)
• [TCOF1 Gene variation in Treacher Collins syndrome and evaluation of speech rehabilitation after bone bridge surgery]. (PMID:37640998)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	tcof1	ENSDARG00000087555
mus_musculus	Tcof1	ENSMUSG00000024613
rattus_norvegicus	Tcof1	ENSRNOG00000026108

Protein

Protein identifiers

Treacle protein — Q13428 (reviewed: Q13428)

Alternative names: Treacher Collins syndrome protein

All UniProt accessions (9): Q13428, A0A2R8Y4M7, A0A2R8Y857, A0A3B3IS06, A0A6I8PRA0, E7ETY2, H0Y8Y7, H0YA99, H0YAB7

UniProt curated annotations — full annotation on UniProt →

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. 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.

Subunit / interactions. Heterodimer; heterodimerizes with NOLC1 following monoubiquitination. Part of a large pre-ribosomal ribonucleoprotein (RNP) complex, that consists of at least 62 ribosomal proteins, 45 nonribosomal proteins and both pre-rRNA and mature rRNA species. Within this complex directly interacts with NOP56 in an RNA-independent manner.

Subcellular location. Nucleus. Nucleolus.

Post-translational modifications. Ubiquitinated. Monoubiquitination by the BCR(KBTBD8) complex promotes the formation of a NOLC1-TCOF1 complex that 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. Pyrophosphorylated by 5-diphosphoinositol pentakisphosphate (5-IP7). Serine pyrophosphorylation is achieved by Mg(2+)-dependent, but enzyme independent transfer of a beta-phosphate from a inositol pyrophosphate to a pre-phosphorylated serine residue.

Disease relevance. 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. The disease is caused by variants affecting the gene represented in this entry.

Miscellaneous. Major. Minor.

Isoforms (8)

UniProt ID	Names	Canonical?
Q13428-1	1	yes
Q13428-2	2
Q13428-3	3
Q13428-4	4
Q13428-5	5
Q13428-6	6
Q13428-7	7
Q13428-8	8

RefSeq proteins (7): NP_000347, NP_001008657, NP_001128715, NP_001128716, NP_001128717, NP_001182070, NP_001358552* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003993	Treacle_dom	Domain
IPR006594	LisH	Conserved_site
IPR017859	Treacle	Family

Pfam: PF03546

UniProt features (127 total): modified residue 68, compositionally biased region 24, cross-link 12, sequence variant 11, splice variant 6, sequence conflict 2, region of interest 2, chain 1, domain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q13428-F1	41.78	0.01

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (80): 725, 732, 755, 755, 1224, 1238, 1248, 1414, 83, 84, 85, 87, 88, 102, 107, 134, 153, 155, 156, 171 …

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 386 (showing top): MORF_RAGE, GOBP_RIBOSOME_BIOGENESIS, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_SKELETAL_SYSTEM_DEVELOPMENT, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_DN, MORF_CDK2, GOBP_RRNA_TRANSCRIPTION, PATIL_LIVER_CANCER, GOBP_TRANSLATION, GOBP_POST_TRANSCRIPTIONAL_REGULATION_OF_GENE_EXPRESSION, MUELLER_PLURINET, GOBP_MESENCHYMAL_CELL_DIFFERENTIATION, MYCMAX_01, BLALOCK_ALZHEIMERS_DISEASE_UP

GO Biological Process (5): skeletal system development (GO:0001501), regulation of translation (GO:0006417), neural crest formation (GO:0014029), neural crest cell development (GO:0014032), nucleolar large rRNA transcription by RNA polymerase I (GO:0042790)

GO Molecular Function (5): RNA binding (GO:0003723), protein-macromolecule adaptor activity (GO:0030674), protein heterodimerization activity (GO:0046982), scaffold protein binding (GO:0097110), protein binding (GO:0005515)

GO Cellular Component (5): fibrillar center (GO:0001650), nucleoplasm (GO:0005654), nucleolus (GO:0005730), cytosol (GO:0005829), nucleus (GO:0005634)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
protein binding	2
nuclear lumen	2
system development	1
translation	1
post-transcriptional regulation of gene expression	1
regulation of protein metabolic process	1
epithelial to mesenchymal transition	1
chordate embryonic development	1
anatomical structure formation involved in morphogenesis	1
neural crest cell differentiation	1
stem cell development	1
transcription by RNA polymerase I	1
rRNA transcription	1
nucleic acid binding	1
molecular adaptor activity	1
protein dimerization activity	1
binding	1
nucleolus	1
intracellular membraneless organelle	1
cytoplasm	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

2266 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TCOF1	POLR1D	P0DPB6	945
TCOF1	NOP56	O00567	919
TCOF1	UBTF	P17480	876
TCOF1	OFD1	O75665	789
TCOF1	LNX2	Q8N448	762
TCOF1	MKLN1	Q9UL63	760
TCOF1	NDST1	P52848	725
TCOF1	TBL1X	O60907	702
TCOF1	POLR1A	O95602	698
TCOF1	RPS14	P06366	686
TCOF1	CDX1	P47902	669
TCOF1	RPS19	P39019	668
TCOF1	POLR1C	O15160	652
TCOF1	SUCLG2	Q96I99	638
TCOF1	SLC26A2	P50443	636

IntAct

113 interactions, top by confidence:

A	B	Type	Score
MED19	MED19	psi-mi:“MI:0914”(association)	0.730
USP44	CETN2	psi-mi:“MI:0914”(association)	0.690
NBN	TCOF1	psi-mi:“MI:0915”(physical association)	0.680
NBN	TCOF1	psi-mi:“MI:0407”(direct interaction)	0.680
PTK2	TGFB1I1	psi-mi:“MI:0914”(association)	0.680
CAMKV	AP3B1	psi-mi:“MI:0914”(association)	0.640
CDK2	GMNN	psi-mi:“MI:0914”(association)	0.640
FGF12	TCOF1	psi-mi:“MI:0914”(association)	0.610
TCOF1	FGF12	psi-mi:“MI:0403”(colocalization)	0.610
TCOF1	FGF12	psi-mi:“MI:2364”(proximity)	0.610
FGF12	TCOF1	psi-mi:“MI:0915”(physical association)	0.610
TOP1	HNRNPR	psi-mi:“MI:0914”(association)	0.600
NOLC1	FGF12	psi-mi:“MI:0914”(association)	0.590
TCOF1	SRPK2	psi-mi:“MI:0217”(phosphorylation reaction)	0.590
ITK	HSP90AA1	psi-mi:“MI:0914”(association)	0.530
PIP4K2A	AP3B1	psi-mi:“MI:0914”(association)	0.530
	TCOF1	psi-mi:“MI:0915”(physical association)	0.490

BioGRID (390): TCOF1 (Affinity Capture-MS), TCOF1 (Affinity Capture-MS), TCOF1 (Affinity Capture-MS), TCOF1 (Affinity Capture-MS), TCOF1 (Affinity Capture-MS), TCOF1 (Affinity Capture-MS), TCOF1 (Affinity Capture-MS), TCOF1 (Affinity Capture-MS), TCOF1 (Proximity Label-MS), TCOF1 (Affinity Capture-MS), TCOF1 (Affinity Capture-MS), TCOF1 (Affinity Capture-MS), TCOF1 (Affinity Capture-MS), TCOF1 (Affinity Capture-MS), TCOF1 (Affinity Capture-MS)

ESM2 similar proteins: A2TJV2, A4FU49, A6NNH2, D6RGX4, O08784, O15446, O54963, O88737, O88778, P0C7V4, P0DV75, P0DV76, P10637, P27546, P27816, P30658, P36225, P41777, P58871, Q13428, Q14676, Q14781, Q149B8, Q3UHD3, Q3UNH4, Q4R729, Q5M7W5, Q5PSV9, Q5TM68, Q5U2M8, Q658T7, Q68A65, Q6NXZ1, Q767L8, Q76KJ5, Q7YR40, Q7Z2K8, Q7Z434, Q8BHW6, Q8N1P7

Diamond homologs: O08784, Q13428

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
TCOF1	“up-regulates activity”	NBN	relocalization
CSNK2A1	“up-regulates activity”	TCOF1	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 115 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Regulation of actin dynamics for phagocytic cup formation	5	12.3×	8e-03
Signaling by BRAF and RAF1 fusions	5	11.4×	8e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

1137 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	160
Likely pathogenic	59
Uncertain significance	432
Likely benign	285
Benign	75

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1068832	NM_001371623.1(TCOF1):c.2709del (p.Lys904fs)	Pathogenic
1069272	NM_001371623.1(TCOF1):c.1504_1505insT (p.Lys502fs)	Pathogenic
1070758	NM_001371623.1(TCOF1):c.2103_2106del (p.Ser701fs)	Pathogenic
1070759	NM_001371623.1(TCOF1):c.4210_4214del (p.Lys1404fs)	Pathogenic
1070982	NM_001371623.1(TCOF1):c.1578del (p.Lys528fs)	Pathogenic
1072690	NC_000005.9:g.(?149775825)(149778631_?)del	Pathogenic
1072904	NM_001371623.1(TCOF1):c.1425_1426del (p.Arg476fs)	Pathogenic
1074227	NM_001371623.1(TCOF1):c.1328_1350del (p.Ala443fs)	Pathogenic
1074353	NM_001371623.1(TCOF1):c.3337_3338insCTCT (p.Gln1113fs)	Pathogenic
1075984	NM_001371623.1(TCOF1):c.3698_3702del (p.Ser1233fs)	Pathogenic
1213100	NM_001371623.1(TCOF1):c.1545del (p.Leu517fs)	Pathogenic
1254492	NM_001371623.1(TCOF1):c.648del (p.Ser217fs)	Pathogenic
127080	NM_001371623.1(TCOF1):c.1637_1640del (p.Glu546fs)	Pathogenic
127081	NM_001371623.1(TCOF1):c.3107dup (p.Ser1036fs)	Pathogenic
1321195	NM_001371623.1(TCOF1):c.1075del (p.Leu359fs)	Pathogenic
1323681	NM_001371623.1(TCOF1):c.4080del (p.Arg1361fs)	Pathogenic
1329860	NM_001371623.1(TCOF1):c.645del (p.Lys215fs)	Pathogenic
1376566	NM_001371623.1(TCOF1):c.2819_2822del (p.Asp940fs)	Pathogenic
1394356	NM_001371623.1(TCOF1):c.4345+2T>C	Pathogenic
1403903	NM_001371623.1(TCOF1):c.462del (p.Lys155fs)	Pathogenic
1422006	NM_001371623.1(TCOF1):c.1622G>A (p.Trp541Ter)	Pathogenic
1442692	NM_001371623.1(TCOF1):c.618_619del (p.Ser206_Ser207insTer)	Pathogenic
1449595	NM_001371623.1(TCOF1):c.1824_1825delinsTT (p.Glu609Ter)	Pathogenic
1451564	NM_001371623.1(TCOF1):c.163C>T (p.Gln55Ter)	Pathogenic
1453106	NM_001371623.1(TCOF1):c.1173del (p.Lys393fs)	Pathogenic
1456141	NM_001371623.1(TCOF1):c.523G>T (p.Glu175Ter)	Pathogenic
1459152	NM_001371623.1(TCOF1):c.109-1del	Pathogenic
1459153	NM_001371623.1(TCOF1):c.1999dup (p.Arg667fs)	Pathogenic
1686255	NM_001371623.1(TCOF1):c.3047-1G>A	Pathogenic
1687307	NM_001371623.1(TCOF1):c.2257C>T (p.Gln753Ter)	Pathogenic

SpliceAI

4810 predictions. Top by Δscore:

Variant	Effect	Δscore
5:150357853:AGGT:A	donor_loss	1.0000
5:150357855:G:GA	donor_loss	1.0000
5:150357856:T:A	donor_loss	1.0000
5:150361212:G:GG	donor_gain	1.0000
5:150364222:G:GT	donor_gain	1.0000
5:150364249:GCCA:G	donor_gain	1.0000
5:150364253:G:GG	donor_gain	1.0000
5:150364280:GC:G	donor_gain	1.0000
5:150368714:A:AG	acceptor_gain	1.0000
5:150368714:AG:A	acceptor_gain	1.0000
5:150368715:G:GA	acceptor_gain	1.0000
5:150368715:GG:G	acceptor_gain	1.0000
5:150368715:GGC:G	acceptor_gain	1.0000
5:150368715:GGCA:G	acceptor_gain	1.0000
5:150368898:GCCTG:G	donor_gain	1.0000
5:150369527:AGG:A	acceptor_gain	1.0000
5:150369528:GGG:G	acceptor_gain	1.0000
5:150369598:TGGAG:T	donor_loss	1.0000
5:150369601:AGG:A	donor_loss	1.0000
5:150369602:GGT:G	donor_loss	1.0000
5:150369603:G:C	donor_loss	1.0000
5:150369604:T:G	donor_loss	1.0000
5:150374613:CCAGG:C	acceptor_loss	1.0000
5:150374615:A:AT	acceptor_loss	1.0000
5:150374616:GGCGA:G	acceptor_gain	1.0000
5:150374789:G:GG	donor_gain	1.0000
5:150374794:G:GT	donor_gain	1.0000
5:150374797:G:GT	donor_gain	1.0000
5:150374808:TCAG:T	donor_loss	1.0000
5:150374809:CAG:C	donor_loss	1.0000

AlphaMissense

9554 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
5:150357799:T:C	L18P	0.999
5:150361204:T:A	W53R	0.999
5:150361204:T:C	W53R	0.999
5:150357775:T:C	L10P	0.998
5:150361206:G:C	W53C	0.998
5:150361206:G:T	W53C	0.998
5:150357787:T:A	I14N	0.996
5:150361205:G:C	W53S	0.996
5:150396465:T:C	L1322P	0.995
5:150357778:T:C	L11P	0.994
5:150357799:T:A	L18Q	0.994
5:150357825:G:C	A27P	0.994
5:150357829:G:C	R28P	0.994
5:150361184:T:A	L46H	0.994
5:150361193:T:A	I49N	0.994
5:150361193:T:G	I49S	0.994
5:150361195:T:G	Y50D	0.994
5:150361208:A:C	Q54P	0.994
5:150357787:T:G	I14S	0.993
5:150357811:G:T	G22V	0.993
5:150357787:T:C	I14T	0.992
5:150357802:T:C	L19P	0.991
5:150357807:G:C	A21P	0.991
5:150357796:A:C	H17P	0.990
5:150357826:C:A	A27E	0.990
5:150361184:T:C	L46P	0.990
5:150396456:T:C	L1319P	0.990
5:150357784:T:C	L13P	0.989
5:150357766:G:C	R7P	0.988
5:150357799:T:G	L18R	0.988

dbSNP variants (sampled 300 via entrez): RS1000013229 (5:150398106 A>G), RS1000122758 (5:150392510 A>G), RS1000174606 (5:150360597 C>T), RS1000277518 (5:150386064 G>C), RS1000369790 (5:150378341 A>G), RS1000453098 (5:150357383 A>G), RS1000456633 (5:150397915 G>A), RS1000639097 (5:150368181 C>A,G), RS1000692827 (5:150367978 G>A), RS1000715656 (5:150368493 T>A), RS1000883158 (5:150361901 T>C), RS1001052104 (5:150355842 G>A), RS1001135183 (5:150388432 T>A), RS1001201737 (5:150357758 C>A,T), RS1001252468 (5:150381302 C>A,G)

Disease associations

OMIM: gene MIM:606847 | disease phenotypes: MIM:154500, MIM:130000, MIM:612998

GenCC curated gene-disease

Disease	Classification	Inheritance
Treacher-Collins syndrome	Definitive	Autosomal dominant
Treacher Collins syndrome 1	Definitive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
Treacher-Collins syndrome	Definitive	AD

Mondo (8): Treacher Collins syndrome 1 (MONDO:0007944), hearing loss disorder (MONDO:0005365), cleft lip/palate (MONDO:0016044), Treacher-Collins syndrome (MONDO:0002457), Ehlers-Danlos syndrome (MONDO:0020066), intellectual disability (MONDO:0001071), Emery-Dreifuss muscular dystrophy 4, autosomal dominant (MONDO:0013071), microcephaly (MONDO:0001149)

Orphanet (5): Treacher-Collins syndrome (Orphanet:861), Cleft lip/palate (Orphanet:199306), Ehlers-Danlos syndrome (Orphanet:98249), Emery-Dreifuss muscular dystrophy (Orphanet:261), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

87 total (30 of 87 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000028	Cryptorchidism
HP:0000046	Small scrotum
HP:0000143	Rectovaginal fistula
HP:0000154	Wide mouth
HP:0000160	Narrow mouth
HP:0000162	Glossoptosis
HP:0000164	Abnormality of the dentition
HP:0000175	Cleft palate
HP:0000185	Cleft soft palate
HP:0000197	Abnormal parotid gland morphology
HP:0000204	Cleft upper lip
HP:0000218	High palate
HP:0000238	Hydrocephalus
HP:0000248	Brachycephaly
HP:0000272	Malar flattening
HP:0000278	Retrognathia
HP:0000294	Low anterior hairline
HP:0000316	Hypertelorism
HP:0000327	Hypoplasia of the maxilla
HP:0000347	Micrognathia
HP:0000356	Abnormality of the outer ear
HP:0000358	Posteriorly rotated ears
HP:0000370	Abnormality of the middle ear
HP:0000377	Abnormal pinna morphology
HP:0000384	Preauricular skin tag
HP:0000405	Conductive hearing impairment
HP:0000413	Atresia of the external auditory canal
HP:0000431	Wide nasal bridge
HP:0000453	Choanal atresia

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST004131_47	Inflammatory bowel disease	3.000000e-15
GCST004132_24	Crohn’s disease	2.000000e-19

MeSH disease descriptors (5)

Descriptor	Name	Tree numbers
D004535	Ehlers-Danlos Syndrome	C14.907.454.240; C15.378.463.515.240; C16.131.831.428; C16.320.850.260; C17.300.200.310; C17.800.804.428; C17.800.827.260
D034381	Hearing Loss	C09.218.458.341; C10.597.751.418.341; C23.888.592.763.393.341
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D008831	Microcephaly	C05.660.207.620; C10.500.507.400.500; C16.131.621.207.620; C16.131.666.507.400.500
C567831	Emery-Dreifuss Muscular Dystrophy 4 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5725056 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 1,538 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL1232461	MOLIBRESIB	2	1,538

PharmGKB: 1 entry (VIP=true, CPIC=false)

ChEMBL bioactivities

4 potent at pChembl≥5 of 4 total, top 4 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.00	IC50	10	nM	MOLIBRESIB
7.75	Kd	18	nM	MOLIBRESIB
5.30	Kd	4983	nM	CHEMBL5653589
5.30	ED50	4983	nM	CHEMBL5653589

PubChem BioAssay actives

3 with measured affinity, of 9 total; 2 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
2-[(4S)-6-(4-chlorophenyl)-8-methoxy-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]-N-ethylacetamide	2178454: Inhibition of TCOF1 (unknown origin) incubated for 1 hr by colloidal coomassie staining based LC-MS/MS analysis	ic50	0.0100	uM
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149565: Binding affinity to human TCOF1 incubated for 45 mins by Kinobead based pull down assay	kd	4.9835	uM

CTD chemical–gene interactions

55 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases expression, decreases methylation, affects cotreatment, affects expression, increases abundance	5
sodium arsenite	decreases expression, affects cotreatment, increases abundance, increases expression	4
Benzo(a)pyrene	affects methylation, decreases methylation, increases expression	3
methacrylaldehyde	increases oxidation, increases abundance, affects cotreatment	2
Acrolein	increases abundance, affects cotreatment, increases oxidation	2
Arsenic	affects cotreatment, increases abundance, increases expression, affects methylation	2
Estradiol	increases expression	2
Ozone	affects cotreatment, increases oxidation, increases abundance	2
Tretinoin	decreases expression	2
aristolochic acid I	increases expression	1
FR900359	affects phosphorylation	1
TAK-243	decreases sumoylation	1
ginger extract	increases abundance, affects cotreatment, affects expression	1
dicrotophos	increases expression	1
testosterone enanthate	affects expression	1
methylmercuric chloride	increases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, increases oxidation, increases abundance	1
methylparaben	increases expression	1
potassium chromate(VI)	increases expression	1
aflatoxin B2	increases methylation	1
cupric chloride	increases expression	1
coumarin	affects phosphorylation	1
di-n-butylphosphoric acid	affects expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
bisphenol B	increases expression	1
2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine	decreases expression, increases response to substance	1
bisphenol S	increases expression	1
LDN 193189	affects cotreatment, decreases expression	1
NSC 689534	affects binding, decreases expression	1

ChEMBL screening assays

8 unique, capped per target: 8 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5652607	Binding	Binding affinity to human TCOF1 incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Cellosaurus cell lines

1 cell lines: 1 induced pluripotent stem cell

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_A8ZG	PSHi002-A	Induced pluripotent stem cell	Male

Clinical trials (associated diseases)

301 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00205881	PHASE4	COMPLETED	Bilateral Benefit in Adult Users of the HiRes 90K Bionic Ear System
NCT00331539	PHASE4	UNKNOWN	Relationship Between Auto NRT and Behavioural T & C Levels With the Nucleus Freedom Cochlear Implant
NCT00424307	PHASE4	UNKNOWN	Bilateral Cochlear Implant Benefit in Young Children
NCT00765635	PHASE4	COMPLETED	Chlorobutanol, Potassium Carbonate, and Irrigation in Cerumen Removal
NCT03321006	PHASE4	COMPLETED	Treating Hearing Loss to Improve Mood and Cognition in Older Adults
NCT01499901	PHASE3	WITHDRAWN	Comparison of the Bilateral Sequential and Simultaneous Cochlear Implantation in the Deaf Children
NCT02561091	PHASE3	COMPLETED	AM-111 in the Treatment of Acute Inner Ear Hearing Loss
NCT03331627	PHASE3	COMPLETED	Safety and Efficacy of STR001-IT and STR001-ER in Patients With SSHL
NCT05532657	PHASE3	ACTIVE_NOT_RECRUITING	ACHIEVE Brain Health Follow-Up Study
NCT00013455	PHASE2	COMPLETED	Quantifying Auditory Perceptual Learning Following Hearing Aid Fitting
NCT00323427	PHASE2	COMPLETED	Clinical Trial of the Living Well With Hearing Loss Workshop
NCT00552786	PHASE2	COMPLETED	Antioxidation Medication for Noise-induced Hearing Loss
NCT00802425	PHASE2	COMPLETED	Efficacy of AM-111 in Patients With Acute Sensorineural Hearing Loss
NCT01139281	PHASE2	COMPLETED	The Protective Effect of Ginkgo Biloba Extract on Cisplatin-induced Ototoxicity in Humans
NCT01451853	PHASE2	UNKNOWN	SPI-1005 for Prevention and Treatment of Chemotherapy Induced Hearing Loss
NCT01588925	PHASE2	COMPLETED	Hearing Preservation Using Dexamethasone and Hyaluronic Acid for Cochlear Implantation
NCT01773278	PHASE2	RECRUITING	Cholesterol and Antioxidant Treatment in Patients With Smith-Lemli-Opitz Syndrome (SLOS)
NCT02832128	PHASE2	COMPLETED	Evaluating Possible Improvement in Speech and Hearing Tests After 28 Days of Dosing of the Study Drug AUT00063 Compared to Placebo (QuicKfire)
NCT04915183	PHASE2	RECRUITING	Atorvastatin to Reduce Cisplatin-Induced Hearing Loss Among Individuals With Head and Neck Cancer
NCT05258773	PHASE2	COMPLETED	Evaluation of the Presence of SENS-401 in the Perilymph
NCT06340633	PHASE2	RECRUITING	SPI-1005 in Adults Receiving Cochlear Implant
NCT00582946	PHASE1	COMPLETED	Wide-Bandwidth Open Canal Hearing Aid For Better Multitalker Speech Understanding
NCT00584155	PHASE1	WITHDRAWN	Protection From Cisplatin Ototoxicity by Lactated Ringers
NCT01206829	PHASE1	UNKNOWN	Hearing Impairment, Cognitive Therapy and Coping
NCT01256229	PHASE1	COMPLETED	Outcomes In Children With Developmental Delay And Deafness
NCT01343394	PHASE1	WITHDRAWN	Safety of Autologous Human Umbilical Cord Blood Mononuclear Fraction to Treat Acquired Hearing Loss in Children
NCT01452607	PHASE1	COMPLETED	Study to Evaluate the Safety and Pharmacokinetics of SPI-1005
NCT02259595	PHASE1	COMPLETED	Study to Determine the Safety, Tolerability, and Pharmacokinetic Profile of HPN-07 and HPN-07 Plus NAC
NCT04041440	PHASE1	COMPLETED	Speech Recognition Training in Children With Hearing Loss
NCT07218913	PHASE1	RECRUITING	Testing the Addition of Pedmark to Cisplatin Chemotherapy for Reducing Drug-Induced Ear Damage in Men With Stage II-III Metastatic Testicular Germ Cell Tumors
NCT04931056	Not specified	COMPLETED	A Post Market Clinical Follow-up Study on Biomet Microfixation HTR PEKK (Midface), Facial & Mandibular Plates.
NCT00486577	PHASE2/PHASE3	COMPLETED	Chronic Electrical Stimulation of the Auditory Cortex for Intractable Tinnitus
NCT00789061	PHASE2/PHASE3	UNKNOWN	Applying Proton Pump Inhibitor to Prevent and Treat Acute Fluctuating Hearing Loss in Patients With SLC26A4 Mutation
NCT01423409	PHASE2/PHASE3	COMPLETED	Multicenter Trial Assessing an Innovative VAS of Pain Among Deaf People
NCT05786378	PHASE2/PHASE3	UNKNOWN	Assessment of The Efficacy of Intratympanic Platelet Rich Plasma for Treatment of Sensorineural Hearing Loss.
NCT01108601	PHASE1/PHASE2	UNKNOWN	Transtympanic Ringer’s Lactate for the Prevention of Cisplatin Ototoxicity
NCT01621256	PHASE1/PHASE2	COMPLETED	Efficacy, Safety, and Tolerability of Ancrod in Patients With Sudden Hearing Loss
NCT06370351	PHASE1/PHASE2	RECRUITING	A Phase I/II Clinical Trial with SENS-501 in Children Suffering from Severe to Profound Hearing Loss Due to Otoferlin (OTOF) Mutations
NCT06545175	PHASE1/PHASE2	RECRUITING	Intracochlear Application of VSF1.01 for the Reduction of Cochlear Implant Surgery Related Trauma
NCT07304024	PHASE1/PHASE2	RECRUITING	A Treatment for a Form of Age-Related Central Auditory Processing Disorder Consisting of Clemastine Fumarate Plus Engineered Sound