BRF1

Summary

BRF1 (BRF1 general transcription factor IIIB subunit, HGNC:11551) is a protein-coding gene on chromosome 14q32.33, encoding Transcription factor IIIB 90 kDa subunit (Q92994). General activator of RNA polymerase which utilizes different TFIIIB complexes at structurally distinct promoters.

This gene encodes one of the three subunits of the RNA polymerase III transcription factor complex. This complex plays a central role in transcription initiation by RNA polymerase III on genes encoding tRNA, 5S rRNA, and other small structural RNAs. The gene product belongs to the TF2B family. Several alternatively spliced variants encoding different isoforms, that function at different promoters transcribed by RNA polymerase III, have been identified.

Source: NCBI Gene 2972 — RefSeq curated summary.

At a glance

• Gene–disease (curated): cerebellar-facial-dental syndrome (Definitive, GenCC) — +1 more curated relationship
• GWAS associations: 13
• Clinical variants (ClinVar): 458 total — 4 pathogenic, 6 likely-pathogenic
• Phenotypes (HPO): 67
• Druggable target: yes
• MANE Select transcript: NM_001519

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11551
Approved symbol	BRF1
Name	BRF1 general transcription factor IIIB subunit
Location	14q32.33
Locus type	gene with protein product
Status	Approved
Aliases	TFIIIB90, BRF, hBRF
Ensembl gene	ENSG00000185024
Ensembl biotype	protein_coding
OMIM	604902
Entrez	2972

Gene structure

Transcript identifiers

Ensembl transcripts: 31 — 25 protein_coding, 5 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000327359, ENST00000379937, ENST00000392557, ENST00000440513, ENST00000446501, ENST00000546417, ENST00000546997, ENST00000547052, ENST00000547374, ENST00000547530, ENST00000547562, ENST00000548421, ENST00000549044, ENST00000549655, ENST00000550208, ENST00000550375, ENST00000550692, ENST00000551787, ENST00000552127, ENST00000635152, ENST00000910238, ENST00000910239, ENST00000910240, ENST00000910241, ENST00000910242, ENST00000910243, ENST00000910244, ENST00000910245, ENST00000910246, ENST00000910247, ENST00000957204

RefSeq mRNA: 7 — MANE Select: NM_001519 NM_001242786, NM_001242787, NM_001242788, NM_001242789, NM_001242790, NM_001519, NM_145685

CCDS: CCDS10001, CCDS42001, CCDS55949, CCDS55950, CCDS55951, CCDS55952, CCDS55953

Canonical transcript exons

ENST00000547530 — 18 exons

Exon	Start	End
ENSE00001311737	105212113	105212164
ENSE00001594930	105226251	105226290
ENSE00001598886	105252507	105252579
ENSE00001672560	105221648	105221914
ENSE00001690016	105226069	105226161
ENSE00001691137	105256518	105256549
ENSE00001745955	105226634	105226760
ENSE00001883333	105209286	105210588
ENSE00002372990	105300446	105301001
ENSE00003476339	105286296	105286376
ENSE00003507270	105219151	105219232
ENSE00003541197	105220069	105220130
ENSE00003556046	105228820	105228913
ENSE00003556090	105211122	105211293
ENSE00003587588	105241265	105241414
ENSE00003674854	105272721	105272894
ENSE00003679981	105218998	105219053
ENSE00003691699	105217544	105217800

Expression profiles

Bgee: expression breadth ubiquitous, 198 present calls, max score 95.36.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 4.2668 / max 108.0679, expressed in 1539 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
145187	5.9931	1712
145181	2.3734	1079
145185	1.5441	962
145186	0.3493	141

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
sural nerve	UBERON:0015488	95.36	gold quality
right uterine tube	UBERON:0001302	92.57	gold quality
right hemisphere of cerebellum	UBERON:0014890	92.26	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	91.85	gold quality
cerebellar hemisphere	UBERON:0002245	91.78	gold quality
cerebellar cortex	UBERON:0002129	91.50	gold quality
adenohypophysis	UBERON:0002196	90.97	gold quality
right frontal lobe	UBERON:0002810	90.82	gold quality
ventricular zone	UBERON:0003053	90.52	gold quality
cortical plate	UBERON:0005343	90.30	gold quality
spinal cord	UBERON:0002240	89.66	gold quality
pituitary gland	UBERON:0000007	89.39	gold quality
cerebellum	UBERON:0002037	89.06	gold quality
ganglionic eminence	UBERON:0004023	88.58	gold quality
apex of heart	UBERON:0002098	88.42	gold quality
granulocyte	CL:0000094	88.34	gold quality
prefrontal cortex	UBERON:0000451	87.84	gold quality
cingulate cortex	UBERON:0003027	87.74	gold quality
anterior cingulate cortex	UBERON:0009835	87.50	gold quality
nucleus accumbens	UBERON:0001882	87.36	gold quality
hindlimb stylopod muscle	UBERON:0004252	87.11	gold quality
mucosa of stomach	UBERON:0001199	87.06	gold quality
gastrocnemius	UBERON:0001388	87.00	gold quality
amygdala	UBERON:0001876	86.98	gold quality
tibial nerve	UBERON:0001323	86.97	gold quality
skin of leg	UBERON:0001511	86.94	gold quality
left ovary	UBERON:0002119	86.93	gold quality
muscle of leg	UBERON:0001383	86.77	gold quality
right ovary	UBERON:0002118	86.74	gold quality
body of uterus	UBERON:0009853	86.56	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.65
E-MTAB-7606	no	236.79

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

25 targeting BRF1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-204-5P	99.79	71.62	2439
HSA-MIR-211-5P	99.79	71.65	2440
HSA-MIR-623	99.76	68.16	1170
HSA-MIR-3934-3P	99.76	65.51	1351
HSA-MIR-4755-5P	99.71	70.34	2716
HSA-MIR-5006-3P	99.71	70.26	2728
HSA-MIR-486-3P	99.51	66.82	1901
HSA-MIR-4498	99.47	67.42	2360
HSA-MIR-6722-3P	99.45	67.62	1919
HSA-MIR-6852-5P	99.17	66.69	2073
HSA-MIR-7160-5P	99.11	67.17	2207
HSA-MIR-1909-3P	99.03	66.56	1662
HSA-MIR-1227-5P	98.65	65.32	1549
HSA-MIR-6893-3P	97.79	64.91	1238
HSA-MIR-6890-3P	97.50	65.71	997
HSA-MIR-939-5P	97.10	65.80	1579
HSA-MIR-370-3P	97.09	64.92	1221
HSA-MIR-346	97.01	66.97	662
HSA-MIR-3194-5P	96.80	64.90	1027
HSA-MIR-1343-5P	96.48	66.06	1506
HSA-MIR-6856-3P	96.47	66.27	781
HSA-MIR-658	88.20	67.03	178
HSA-MIR-3195	88.05	57.43	53

Literature-anchored findings (GeneRIF, showing 34)

• CK2 forms a stable complex with TFIIIB and activates RNA polymerase III transcription in human cells. (PMID:11997511)
• human small nuclear RNA gene-specific transcription factor IIIB complex de novo on and off promoter (PMID:12016223)
• BRF1 accelerated mRNA decay and antagonized the stabilizing effect of PI3-kinase, while mutation of the zinc fingers abolished both function and ARE-binding activity. This approach identifies BRF1 as an essential regulator of ARE-dependent mRNA decay. (PMID:12198173)
• Data report that protein kinase B (PKB/Akt) stabilizes ARE transcripts by phosphorylating butyrate response factor (BRF1) at serine 92. (PMID:15538381)
• These results suggest a direct role of an RNA polymerase III transcription factor in the targeting process. (PMID:16982688)
• depletion of endogenous TTP and BRF-1 proteins, or overexpression of dominant-negative mutant TTP proteins, impairs the localization of reporter AU-rich element mRNAs (PMID:17369404)
• Maf1 occupancy of Pol III genes is inversely correlated with that of the initiation factor TFIIIB (subunit Brf1) and Pol III. (PMID:17499043)
• the hypo-phosphorylated Rb appeared to be largely sequestered into a complex with Brf1, which resulted in the blockage of Rb function to repress E2F1 transactivation (PMID:17877750)
• Brf1 gene was identified in the genome-wide loss-of-function genetic screen as putative tumor suppressor located at 14q32.33. (PMID:17968325)
• MK2-mediated inhibition of BRF1 requires phosphorylation at S54, S92, and S203. (PMID:18326031)
• deregulation of Brf1 and Brf2 expression could be a key mechanism responsible for the observed deregulation of RNA pol III transcription in cancer cells (PMID:18700021)
• results identify a human Pol III isoform and isoform-specific functions in the regulation of cell growth and transformation (PMID:20154270)
• Alcohol induces RNA polymerase III-dependent transcription through c-Jun by co-regulating TATA-binding protein (TBP) and Brf1 expression. (PMID:21106530)
• these observations are in favor of a cell- and context-dependent regulation of Tis11b by hypoxia, which then contributes to modulation of angiogenesis. (PMID:21832157)
• hnRNP F is a co-factor in a subset of tristetraprolin/BRF1/BRF2-mediated mRNA decay. (PMID:24978456)
• BRF1 mutations that reduce protein activity cause neurodevelopmental anomalies, suggesting that BRF1-mediated Pol III transcription is required for normal cerebellar and cognitive development. (PMID:25561519)
• Brf1 expression is increased in human HCC cases, which is correlated with shorter survival times. (PMID:26701855)
• Site-directed mutagenesis combined with kinase assays and specific phosphosite immunodetection identified Ser-54 (S54) and Ser-334 (S334) as PKA target amino acids in vitro and in vivo. Phosphomimetic mutation of the C-terminal S334 markedly increased TIS11b half-life and, unexpectedly, enhanced TIS11b activity on mRNA decay. (PMID:27708140)
• Mutations in BRF1 cause severe short stature, remarkably delayed bone age, dysmorphic features, cerebellar hypoplasia and cognitive dysfunction inherited in an autosomal recessive pattern. (PMID:27748960)
• In an analysis of families with a history of colorectal cancer, we associated germline mutations in BRF1 with predisposition to colorectal cancer. Seven of the identified variants (1 detected in 2 families) affected BRF1 mRNA splicing, protein stability, or expression and/or function. (PMID:28912018)
• These results indicate an interaction between Brf1 and ER alpha, which synergistically regulates the transcription of Pol III genes. (PMID:28972307)
• These findings uncover a novel mechanism for the regulation of BRF1 and reveal RNF12 as an important regulator of Pol III-dependent transcription. (PMID:30413534)
• A derivative of TIS11b called R9-ZnC(S334D), by combining N-terminal domain deletion, serine-to-aspartate substitution at position 334 to enhance the function of the protein and fusion to the cell-penetrating peptide polyarginine R9. R9-ZnC(S334D) not only blunted secretion of vascular endothelial growth factor (VEGF) but also inhibited proliferation, migration, invasion, and anchorage-independent growth of breast cancer. (PMID:30914800)
• results provide evidence that AMD surveils poly(A)(+) Replication-dependent histone mRNAs via BRF1-mediated degradation under physiological conditions. (PMID:30962286)
• BRF1 accelerates prostate tumourigenesis and perturbs immune infiltration. (PMID:31740786)
• Recent studies have demonstrated that Brf1 is overexpressed in most ER+ (estrogen receptor positive) cases of breast cancer and the change in cellular levels of Brf1 reflects the therapeutic efficacy and prognosis of this disease. It suggests that Brf1 may be a potential diagnosis biomarker and a therapeutic target of alcohol-associated breast cancer. (PMID:31781337)
• The transcription factor Sp1 modulates RNA polymerase III gene transcription by controlling BRF1 and GTF3C2 expression in human cells. (PMID:32115405)
• Runx2 mediates the deregulation of Brf1 and Pol III genes and its abnormal expression predicts the worse prognosis of breast cancer. (PMID:32198086)
• Expanding the phenotype of cerebellar-facial-dental syndrome: Two siblings with a novel variant in BRF1. (PMID:32896090)
• Cerebellofaciodental syndrome in an adult patient: Expanding the phenotypic and natural history characteristics. (PMID:33645901)
• Comprehensive Analysis of Prognostic and Genetic Signatures for General Transcription Factor III (GTF3) in Clinical Colorectal Cancer Patients Using Bioinformatics Approaches. (PMID:33925358)
• tRNA biogenesis and specific aminoacyl-tRNA synthetases regulate senescence stability under the control of mTOR. (PMID:34928935)
• A novel BRF1 mutation in two middle-aged siblings with cerebellofaciodental syndrome. (PMID:34935685)
• TFIIB-related factor 1 is a nucleolar protein that promotes RNA polymerase I-directed transcription and tumour cell growth. (PMID:35925837)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	brf1b	ENSDARG00000005002
mus_musculus	Brf1	ENSMUSG00000011158
rattus_norvegicus	Brf1	ENSRNOG00000014595
drosophila_melanogaster	Brf	FBGN0038499
caenorhabditis_elegans		WBGENE00000271

Paralogs (2): BRF2 (ENSG00000104221), GTF2B (ENSG00000137947)

Protein

Protein identifiers

Transcription factor IIIB 90 kDa subunit — Q92994 (reviewed: Q92994)

Alternative names: B-related factor 1, TAF3B2, TATA box-binding protein-associated factor, RNA polymerase III, subunit 2

All UniProt accessions (9): Q92994, F8VS45, F8VWT8, F8VWY1, F8VXJ4, F8W123, H0YIV6, Q3SYD7, V9HVY2

UniProt curated annotations — full annotation on UniProt →

Function. General activator of RNA polymerase which utilizes different TFIIIB complexes at structurally distinct promoters. The isoform 1 is involved in the transcription of tRNA, adenovirus VA1, 7SL and 5S RNA. Isoform 2 is required for transcription of the U6 promoter.

Subunit / interactions. TFIIIB comprises at least the TATA-binding protein (TBP) and the B-related factor 1 (BRF1/TFIIIB90). Interacts with BDP1. Interacts with MAF1.

Subcellular location. Nucleus.

Disease relevance. Cerebellofaciodental syndrome (CFDS) [MIM:616202] An autosomal recessive disorder characterized by cerebellar hypoplasia, delayed development and intellectual disability, as well as facial dysmorphic features, short stature, microcephaly, and dental anomalies. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the TFIIB family.

Isoforms (9)

UniProt ID	Names	Canonical?
Q92994-1	1, hBRF1	yes
Q92994-2	2, hBRF2
Q92994-3	3, hBRF3
Q92994-4	4, hBRF4
Q92994-5	5
Q92994-6	6
Q92994-7	7
Q92994-8	8
Q92994-9	9

RefSeq proteins (7): NP_001229715, NP_001229716, NP_001229717, NP_001229718, NP_001229719, NP_001510, NP_663718 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000812	TFIIB	Family
IPR011665	BRF1_TBP-bd_dom	Domain
IPR013137	Znf_TFIIB	Domain
IPR013150	TFIIB_cyclin	Domain
IPR013763	Cyclin-like_dom	Domain
IPR036915	Cyclin-like_sf	Homologous_superfamily

Pfam: PF00382, PF07741, PF08271

UniProt features (42 total): splice variant 11, sequence conflict 10, sequence variant 5, binding site 4, region of interest 4, modified residue 3, repeat 2, chain 1, zinc finger region 1, compositionally biased region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q92994-F1	70.22	0.31

Functional residue map

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

Ligand- & substrate-binding residues (4): 9; 25; 28; 6

Post-translational modifications (3): 365, 450, 553

Function

Pathways and Gene Ontology

Reactome pathways

6 pathways

ID	Pathway
R-HSA-749476	RNA Polymerase III Abortive And Retractive Initiation
R-HSA-76061	RNA Polymerase III Transcription Initiation From Type 1 Promoter
R-HSA-76066	RNA Polymerase III Transcription Initiation From Type 2 Promoter
R-HSA-74158	RNA Polymerase III Transcription
R-HSA-74160	Gene expression (Transcription)
R-HSA-76046	RNA Polymerase III Transcription Initiation

MSigDB gene sets: 300 (showing top): SHEPARD_BMYB_MORPHOLINO_UP, WANG_CLIM2_TARGETS_UP, SHEPARD_CRASH_AND_BURN_MUTANT_UP, GOBP_TRNA_METABOLIC_PROCESS, GOBP_TRANSCRIPTION_BY_RNA_POLYMERASE_III, DARWICHE_SKIN_TUMOR_PROMOTER_DN, DARWICHE_PAPILLOMA_RISK_LOW_DN, DARWICHE_PAPILLOMA_RISK_HIGH_DN, DARWICHE_SQUAMOUS_CELL_CARCINOMA_DN, GOBP_RRNA_TRANSCRIPTION, MODULE_285, GOBP_DNA_TEMPLATED_TRANSCRIPTION_INITIATION, GOBP_PROTEIN_DNA_COMPLEX_ORGANIZATION, chr14q32, GOCC_PROTEIN_DNA_COMPLEX

GO Biological Process (6): DNA-templated transcription initiation (GO:0006352), transcription by RNA polymerase III (GO:0006383), transcription initiation at RNA polymerase III promoter (GO:0006384), rRNA transcription (GO:0009303), tRNA transcription (GO:0009304), transcription preinitiation complex assembly (GO:0070897)

GO Molecular Function (6): RNA polymerase III general transcription initiation factor activity (GO:0000995), RNA polymerase III type 3 promoter sequence-specific DNA binding (GO:0001006), zinc ion binding (GO:0008270), TBP-class protein binding (GO:0017025), protein binding (GO:0005515), metal ion binding (GO:0046872)

GO Cellular Component (4): transcription factor TFIIIB complex (GO:0000126), nucleus (GO:0005634), nucleoplasm (GO:0005654), transcription preinitiation complex (GO:0097550)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
RNA Polymerase III Transcription	2
RNA Polymerase III Transcription Initiation	2
Gene expression (Transcription)	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
DNA-templated transcription	4
DNA-templated transcription initiation	2
transcription by RNA polymerase III	2
RNA biosynthetic process	1
rRNA metabolic process	1
tRNA metabolic process	1
protein-DNA complex assembly	1
general transcription initiation factor activity	1
RNA polymerase III cis-regulatory region sequence-specific DNA binding	1
transition metal ion binding	1
general transcription initiation factor binding	1
binding	1
cation binding	1
RNA polymerase III transcription regulator complex	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
cellular anatomical structure	1
protein-DNA complex	1

Protein interactions and networks

STRING

1026 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
BRF1	GTF3C1	Q12789	981
BRF1	GTF3C5	Q9Y5Q8	890
BRF1	BDP1	A6H8Y1	879
BRF1	GTF3C3	Q9Y5Q9	870
BRF1	GTF3C4	Q9UKN8	860
BRF1	TBP	P20226	840
BRF1	GTF3A	Q92664	779
BRF1	POLR3F	Q9H1D9	667
BRF1	HMGB2	P26583	654
BRF1	POLR3C	Q9BUI4	626
BRF1	GTF2B	Q00403	532
BRF1	POLR3D	P05423	531
BRF1	TAF1B	Q53T94	506
BRF1	POLR1C	O15160	492
BRF1	RRN3	Q9NYV6	480

IntAct

28 interactions, top by confidence:

A	B	Type	Score
CXCR4	TMEM120B	psi-mi:“MI:0914”(association)	0.530
BRF1		psi-mi:“MI:0915”(physical association)	0.370
BRF1	PCBD2	psi-mi:“MI:0915”(physical association)	0.370
Rab5c		psi-mi:“MI:0914”(association)	0.350
Gpsm1	OARD1	psi-mi:“MI:0914”(association)	0.350
ACSL4	ACSL3	psi-mi:“MI:0914”(association)	0.350
Eef1a1	ERLIN2	psi-mi:“MI:0914”(association)	0.350
Vbp1	BAP1	psi-mi:“MI:0914”(association)	0.350
TBP	DYRK1A	psi-mi:“MI:0914”(association)	0.350
POLR3E	BDP1	psi-mi:“MI:0914”(association)	0.350
TCF20	MTA3	psi-mi:“MI:0914”(association)	0.350
VPS50	PHF20L1	psi-mi:“MI:0914”(association)	0.350
CAPZB	ENAH	psi-mi:“MI:0914”(association)	0.350
LMNA	CLIC1	psi-mi:“MI:0914”(association)	0.350
POLR1C	BDP1	psi-mi:“MI:0914”(association)	0.350
POLR1D	BDP1	psi-mi:“MI:0914”(association)	0.350
POLR2F	BDP1	psi-mi:“MI:0914”(association)	0.350
POLR2H	BDP1	psi-mi:“MI:0914”(association)	0.350
POLR2K	BDP1	psi-mi:“MI:0914”(association)	0.350
POLR3B	BDP1	psi-mi:“MI:0914”(association)	0.350
POLR3F	BDP1	psi-mi:“MI:0914”(association)	0.350
TBP	BDP1	psi-mi:“MI:0914”(association)	0.350
LDLRAD1	GXYLT2	psi-mi:“MI:0914”(association)	0.350
CLEC4C	SLC25A6	psi-mi:“MI:0914”(association)	0.350
BRF1	DTNBP1	psi-mi:“MI:0915”(physical association)	0.000
TBP	BRF1	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (121): BRF1 (Affinity Capture-MS), BRF1 (Affinity Capture-MS), BRF1 (Affinity Capture-MS), BRF1 (Affinity Capture-MS), BRF1 (Affinity Capture-MS), BRF1 (Affinity Capture-MS), BRF1 (Affinity Capture-MS), BRF1 (Affinity Capture-MS), BRF1 (Affinity Capture-MS), BRF1 (Reconstituted Complex), BRF1 (Affinity Capture-Western), TBP (Affinity Capture-Western), BRF1 (Co-localization), BRF1 (Co-localization), BRF1 (Co-localization)

ESM2 similar proteins: A0JPP7, E9Q4Z2, F1N2W9, F1QDI9, O12940, O35815, O60784, O70593, O88746, O88978, O88984, O95453, P54252, P54731, P58797, P69341, Q0VGM9, Q1RMR5, Q28BP9, Q2HJD0, Q2T9Z1, Q32LM2, Q3TDN2, Q5BK32, Q5R752, Q5RC51, Q5RJZ1, Q68FJ8, Q6AZH6, Q6GQ69, Q6H1L8, Q6R005, Q6TH22, Q7ZU92, Q7ZYA7, Q80W98, Q8BJU0, Q8CFK2, Q8UUU2, Q8VD33

Diamond homologs: A0B5T8, A1RV37, A3CSQ6, A4G0F2, A4WMA6, A5UKA1, A6UW60, A6VI28, A7IAR4, A8AC96, A8MCX6, A9A8Q0, B1YCX0, B8GJQ9, O13749, O16991, O23215, O26971, O28970, O59151, P0CW14, P0CW15, P29052, P29054, P42198, P46221, P48512, P48513, P50387, P58109, P58110, P58111, P61998, P61999, P62915, P62916, Q00403, Q2KIN8, Q2NEL6, Q4R3J5

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
BRF1	“form complex”	TFIIIB	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 36 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
RNA Polymerase III Chain Elongation	8	203.0×	2e-16
RNA Polymerase III Transcription Initiation From Type 2 Promoter	10	169.2×	3e-19
RNA Polymerase III Transcription Initiation From Type 1 Promoter	10	163.1×	3e-19
RNA Polymerase III Transcription Initiation From Type 3 Promoter	10	163.1×	3e-19
RNA Polymerase III Transcription Termination	8	158.9×	2e-15
RNA Polymerase III Transcription Initiation	10	134.3×	2e-18
RNA Polymerase III Transcription	10	130.5×	2e-18
RNA Polymerase III Abortive And Retractive Initiation	10	111.4×	1e-17

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	4
Likely pathogenic	6
Uncertain significance	266
Likely benign	119
Benign	15

Top pathogenic / likely-pathogenic (10)

Variant ID	HGVS	Classification
1098377	NM_001519.4(BRF1):c.876dup (p.Ser293fs)	Pathogenic
161425	NM_001519.4(BRF1):c.667C>T (p.Arg223Trp)	Pathogenic
2223631	NM_001519.4(BRF1):c.1649del (p.Gly550fs)	Pathogenic
3135032	NM_001519.4(BRF1):c.794_795insTTTA (p.Glu266fs)	Pathogenic
1077071	NM_001519.4(BRF1):c.793_794delinsCATTTA (p.Thr265fs)	Likely pathogenic
1098378	NM_001519.4(BRF1):c.875C>G (p.Pro292Arg)	Likely pathogenic
1180555	NM_001519.4(BRF1):c.1954G>A (p.Gly652Arg)	Likely pathogenic
2136288	NM_001519.4(BRF1):c.419G>C (p.Cys140Ser)	Likely pathogenic
2630025	NM_001519.4(BRF1):c.1456_1457del (p.Arg486fs)	Likely pathogenic
2630302	NM_001519.4(BRF1):c.291del (p.Asn98fs)	Likely pathogenic

SpliceAI

0 predictions. Top by Δscore:

AlphaMissense

4438 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
14:105226709:G:C	F280L	1.000
14:105226709:G:T	F280L	1.000
14:105226710:A:G	F280S	1.000
14:105226711:A:G	F280L	1.000
14:105226758:A:G	L264P	1.000
14:105228820:C:A	R263M	1.000
14:105241270:C:T	G230E	1.000
14:105241272:G:C	C229W	1.000
14:105241312:C:G	R216P	1.000
14:105241330:A:G	L210P	1.000
14:105241339:G:T	A207D	1.000
14:105241389:A:C	F190L	1.000
14:105241389:A:T	F190L	1.000
14:105241390:A:G	F190S	1.000
14:105241391:A:G	F190L	1.000
14:105241411:G:T	P183Q	1.000
14:105252530:A:G	L174P	1.000
14:105256543:A:G	L149P	1.000
14:105256543:A:T	L149H	1.000
14:105272739:G:T	R141S	1.000
14:105272740:G:C	C140W	1.000
14:105272741:C:T	C140Y	1.000
14:105272742:A:G	C140R	1.000
14:105272747:A:G	L138P	1.000
14:105272751:A:C	Y137D	1.000
14:105272755:G:C	C135W	1.000
14:105272756:C:T	C135Y	1.000
14:105272757:A:G	C135R	1.000
14:105272759:G:T	A134D	1.000
14:105272762:G:T	A133D	1.000

dbSNP variants (sampled 300 via entrez): RS1000010741 (14:105274463 G>A,C), RS1000011184 (14:105228181 A>G,T), RS1000022712 (14:105269755 C>A,T), RS1000029395 (14:105312315 T>C), RS1000035406 (14:105223063 C>A,G), RS1000039643 (14:105242401 A>C,G), RS1000102669 (14:105313581 G>A), RS1000124018 (14:105229525 G>A,C), RS1000179779 (14:105261620 C>T), RS1000195759 (14:105211620 C>A,T), RS1000196457 (14:105246501 GCT>G), RS1000211837 (14:105297450 G>C), RS1000211894 (14:105281525 T>C), RS1000239484 (14:105216907 A>C,G), RS1000250251 (14:105246703 C>A)

Disease associations

OMIM: gene MIM:604902 | disease phenotypes: MIM:616202, MIM:618067, MIM:114500, MIM:619681

GenCC curated gene-disease

Disease	Classification	Inheritance
cerebellar-facial-dental syndrome	Definitive	Autosomal recessive
colorectal adenoma	Limited	Autosomal dominant

Mondo (7): cerebellar-facial-dental syndrome (MONDO:0014529), developmental and epileptic encephalopathy, 66 (MONDO:0054845), colorectal cancer (MONDO:0005575), dystonia, early-onset, and/or spastic paraplegia (MONDO:0859215), intellectual disability (MONDO:0001071), sensorineural hearing loss disorder (MONDO:0020678), colorectal adenoma (MONDO:0005484)

Orphanet (3): Cerebellar-facial-dental syndrome (Orphanet:444072), NON RARE IN EUROPE: Colorectal cancer (Orphanet:466667), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

67 total (30 of 67 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000023	Inguinal hernia
HP:0000028	Cryptorchidism
HP:0000074	Ureteropelvic junction obstruction
HP:0000126	Hydronephrosis
HP:0000252	Microcephaly
HP:0000343	Long philtrum
HP:0000347	Micrognathia
HP:0000369	Low-set ears
HP:0000384	Preauricular skin tag
HP:0000431	Wide nasal bridge
HP:0000463	Anteverted nares
HP:0000470	Short neck
HP:0000486	Strabismus
HP:0000518	Cataract
HP:0000675	Macrodontia of permanent maxillary central incisor
HP:0000679	Taurodontia
HP:0000689	Dental malocclusion
HP:0000718	Aggressive behavior
HP:0000750	Delayed speech and language development
HP:0000954	Single transverse palmar crease
HP:0001182	Tapered finger
HP:0001249	Intellectual disability
HP:0001256	Mild intellectual disability
HP:0001263	Global developmental delay
HP:0001321	Cerebellar hypoplasia
HP:0001508	Failure to thrive
HP:0001601	Laryngomalacia
HP:0001629	Ventricular septal defect
HP:0001634	Mitral valve prolapse

GWAS associations

13 associations (top):

Study	Trait	p-value
GCST001335_27	Mean platelet volume	3.000000e-11
GCST004599_176	Mean platelet volume	2.000000e-28
GCST004603_229	Platelet count	1.000000e-14
GCST004616_59	Platelet distribution width	3.000000e-09
GCST004691_9	Huntington’s disease progression	3.000000e-06
GCST005991_37	Platelet count	4.000000e-08
GCST90002390_280	Mean corpuscular hemoglobin	2.000000e-14
GCST90002392_467	Mean corpuscular volume	9.000000e-22
GCST90002395_219	Mean platelet volume	4.000000e-80
GCST90002396_627	Mean reticulocyte volume	5.000000e-15
GCST90002397_373	Mean spheric corpuscular volume	7.000000e-29
GCST90002402_156	Platelet count	3.000000e-43
GCST90002403_474	Red blood cell count	5.000000e-15

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0004309	platelet count
EFO:0007984	platelet component distribution width
EFO:0008336	disease progression measurement
EFO:0004527	mean corpuscular hemoglobin
EFO:0010701	mean reticulocyte volume
EFO:0004305	erythrocyte count

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4523421 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

29 total (human), top 29 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases methylation, increases expression	2
sodium arsenite	affects methylation, decreases expression	2
Resveratrol	decreases expression	2
Air Pollutants	decreases expression, increases abundance, increases expression	2
Ethanol	decreases reaction, increases expression, increases reaction	2
Aflatoxin B1	increases methylation	2
Particulate Matter	decreases expression, increases abundance, increases expression	2
FR900359	increases phosphorylation	1
benzo(e)pyrene	increases methylation	1
ferrous chloride	decreases expression	1
coumarin	increases phosphorylation	1
methacrylaldehyde	affects cotreatment, increases expression	1
CGP 52608	affects binding, increases reaction	1
Grape Seed Proanthocyanidins	affects cotreatment, decreases expression	1
Acrolein	affects cotreatment, increases expression	1
Benzo(a)pyrene	decreases methylation	1
Betaine	decreases reaction, increases expression	1
Caffeine	affects phosphorylation	1
Carmustine	decreases expression	1
Catechin	affects cotreatment, decreases expression	1
Diazinon	increases methylation	1
Doxorubicin	affects reaction, increases cleavage	1
Ellagic Acid	decreases expression	1
Methapyrilene	increases methylation	1
Ozone	affects cotreatment, increases expression	1
Phthalic Acids	increases methylation	1
Smoke	decreases expression	1
Valproic Acid	increases methylation	1
Sodium Selenite	decreases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4377340	Binding	Binding affinity to BRRF1 (unknown origin) assessed as induction of thermal shifts at 200 uM measured for 25 mins by SYPRO orange dye thermal shift assay	Discovery of a Potent and Selective Fragment-like Inhibitor of Methyllysine Reader Protein Spindlin 1 (SPIN1). — J Med Chem

Cellosaurus cell lines

3 cell lines: 3 embryonic stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_A0J8	SEES3-1V human BRF1, clone1	Embryonic stem cell	Male
CVCL_A0J9	SEES3-1V human BRF1, clone2	Embryonic stem cell	Male
CVCL_A0K0	SEES3-1V human BRF1, clone3	Embryonic stem cell	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT01767870	PHASE4	UNKNOWN	Efficacy Combined Fecal Immunochemical Test-Sigmoidoscopy for the Detection of Advanced Colorectal Neoplasia
NCT07167342	PHASE4	RECRUITING	The Effect of Oral Clostridium Butyricum on the Recurrence After Colonoscopic Resection of Colorectal Adenoma
NCT00114829	PHASE4	UNKNOWN	Preoperative Assessment of Colon Tumor
NCT00114842	PHASE4	COMPLETED	Magnetic Resonance (MR) Colonography With Fecal Tagging
NCT00114946	PHASE4	TERMINATED	A Study to Compare Two Avastin-Based Treatment Regimens for the Treatment of Metastatic Colorectal Cancer
NCT00122720	PHASE4	COMPLETED	The Effect of Darbepoetin Upon Rehabilitation for Colorectal Cancer Surgery
NCT00129870	PHASE4	TERMINATED	CONCEPT: Comparison of Oxaliplatin vs Conventional Methods With Calcium/Magnesium in First-Line Metastatic Colorectal Cancer
NCT00138060	PHASE4	COMPLETED	Toxicity/Benefit Ratio Optimization of Chemotherapy in Colorectal Cancer (CRC) Patients by Determination of Individual Genotypic Determinants
NCT00216424	PHASE4	TERMINATED	Capecitabine (Xeloda) and Radiation for Patients With Rectosigmoid Carcinoma
NCT00327093	PHASE4	TERMINATED	Elaboration of a Model for Predicting Efficacy of Monoclonal Antibodies (Cetuximab and Bevacizumab) in Patients With Colorectal Cancer and Liver Metastases
NCT00332943	PHASE4	COMPLETED	MR Colonography With Fecal Tagging. Barium vs. BariumFerumoxsil
NCT00441311	PHASE4	COMPLETED	Dissemination of Colorectal Cancer Screening to Primary Care Physicians
NCT00460837	PHASE4	WITHDRAWN	Comparison of Bowel Preparation in Virtual Colonoscopy (VC) - Patient Experience
NCT00473980	PHASE4	COMPLETED	Preoperative Non-steroidal Anti-inflammatory Drugs(NSAID) to Colorectal Cancer Patients
NCT00488904	PHASE4	COMPLETED	Omega-3 Fatty Acids and Postoperative Complications After Colorectal Surgery
NCT00496678	PHASE4	COMPLETED	Trial of Patient Navigation-Activation
NCT00502671	PHASE4	COMPLETED	A Study of Xeloda (Capecitabine) as Adjuvant Monotherapy in Patients With Colon Cancer.
NCT00559676	PHASE4	COMPLETED	Study of Biomarkers in Patients Undergoing Chemotherapy for Metastatic Colorectal Cancer
NCT00577031	PHASE4	COMPLETED	OBELIX Study: A Study of Avastin (Bevacizumab) in Combination With XELOX in Patients With Metastatic Cancer of the Colon or Rectum.
NCT00626054	PHASE4	COMPLETED	Comparison of Two Methods of Administration of a PEG Solution
NCT00812864	PHASE4	COMPLETED	Pharmacokinetic Study of Capecitabine in Elderly Cancer Patient (≥ 75 Years)
NCT00868569	PHASE4	UNKNOWN	Transhepatic Arterial Chemotherapy (TAC) Versus Transcatheter Arterial Chemoembolization (TACE) Plus Folfox4 as the Treatment of Unresectable Liver Metastasis of Colorectal Cancer
NCT00868816	PHASE4	COMPLETED	Oxaliplatine Based Adjuvant Chemotherapy for Stage II/III Colorectal Cancer: 8 Cycles Versus 12 Cycles
NCT00874406	PHASE4	UNKNOWN	Preoperative Transhepatic Arterial Chemotherapy (TAC) in the Treatment of Liver Metastasis of Resectable Colorectal Cancer
NCT00928928	PHASE4	COMPLETED	Oxidative Stress Markers in Open and Laparoscopic Colectomy for Cancer
NCT00942461	PHASE4	COMPLETED	Inflammatory Response in Laparoscopic and Open Colectomy
NCT01023633	PHASE4	UNKNOWN	OPTIMOX1 in Chinese mCRC Patients
NCT01271582	PHASE4	UNKNOWN	Investigation of Association Between UGT1A1 Polymorphisms and Irinotecan Toxicity in Korean Patients
NCT01315990	PHASE4	UNKNOWN	FOLFIRI in Combination With Cetuximab in the First-line Treatment of Metastatic Colorectal Cancer Including a Regular Dermal Prophylaxis to Prevent Acneiforme Follicular Exanthema
NCT01493713	PHASE4	COMPLETED	Correlation Between RECIST, Morphologic Response by CT- Histopathologic Response in Hepatic Metastasis Secondary to Colorectal Cancer
NCT01609660	PHASE4	COMPLETED	Impact of Probiotics on the Intestinal Microbiota
NCT01641458	PHASE4	COMPLETED	Pharmacology-driven Dosing of Fluoropyrimidines in Cancer Patients
NCT01689792	PHASE4	COMPLETED	A Multi-centre Study Comparing the Polyp Detection Rate of Two Different Types of Bowel Preparation: a 2-litre Solution (MOVIPREP®) Versus a Hyperosmotic and Stimulant Combined Low Volume Bowel Preparation (Sodium Picosulfate and Magnesium Citrate)
NCT01695772	PHASE4	COMPLETED	A Study of Bevacizumab Plus 5-Flurouracil (5-FU) Based Doublet Chemotherapy as Neoadjuvant Therapy for Participants With Previously Untreated Unresectable Liver-Only Metastases From Colorectal Cancer
NCT01695863	PHASE4	COMPLETED	Efficacy and Patient Satisfaction of Miralax and Gatorade Versus Movi Prep
NCT01706822	PHASE4	TERMINATED	Radial Reload Laparoscopic LAR Case Series
NCT01740947	PHASE4	TERMINATED	Does Administration of Antibiotics in Patients Undergoing Surgery for Colorectal Cancer Result in Less Complications and Better Prognosis?
NCT01831310	PHASE4	COMPLETED	Nutrition for Colorectal Cancer Patients and Neutrophil Functions
NCT01841294	PHASE4	UNKNOWN	NK Activity Modulation Induced by Intravenous Lidocaine During Colorectal Laparoscopic Surgery
NCT01959061	PHASE4	UNKNOWN	Efficacy and Safety of Raltitrexed-based Transarterial Chemoembolisation(TACE)for Colorectal Cancer Liver Metastases