BRF1

protein-coding

BRF1 RNA polymerase III transcription initiation factor subunit, the group of General transcription factor IIIB complex subunits |General transcription factors

Gene summary

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. [provided by RefSeq, Jun 2011]

Previous symbols:

TAF3B2
TAF3C
GTF3B

MANE transcript

NM_001519.4

Inheritance

AD, AR

ClinVar variants

P:16U:130B:80

Top phenotype

Cerebellofaciodental syndrome

gnomAD constraint

pLI —, LoF o/e 0.38

Max pathogenic AF

—

Genomic locus

chr14:105,209,286-105,315,589

External References & Databases

Ensembl (ENSG00000185024)

Transcript & Mutation Effects

hg38 • Region Span ~106.3 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

colorectal adenomaLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0005484

Submitter: Ambry Genetics

cerebellar-facial-dental syndromeMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0014529

Submitter: Ambry Genetics

cerebellar-facial-dental syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014529

Submitter: PanelApp Australia

cerebellar-facial-dental syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014529

Submitter: Labcorp Genetics (formerly Invitae)

cerebellar-facial-dental syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014529

Submitter: Orphanet

cerebellar-facial-dental syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014529

Submitter: G2P

Clinical Genomic Database (CGD)

Cerebellofaciodental syndromeAR

Manifestation: Audiologic/Otolaryngologic; Craniofacial; Dental; Musculoskeletal; Neurologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 25561519

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to BRF1 variants in ClinVar

15 Conditions Cataloged

Inborn genetic diseasesTotal: 133

not providedTotal: 101

not specifiedTotal: 92

Cerebellar-facial-dental syndromeTotal: 17

BRF1-related disorderTotal: 11

Dystonia, early-onset, and/or spastic paraplegiaTotal: 2

Intellectual disabilityTotal: 2

See casesTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001519.4. 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				54 clinvar	3 clinvar	57
missense	1 clinvar	7 clinvar	126 clinvar	23 clinvar		157
nonsense		1 clinvar				1
start loss						0
frameshift	3 clinvar	4 clinvar				7
splice donor/acceptor (+/-2bp)			4 clinvar			4
Total	4	12	130	77	3	226

Highest pathogenic variant AF is 0.00012713004

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 64 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001519.4	RefSeq	NP_001510.2	18	MANE Select
ENST00000547530.7	Ensembl	ENSP00000448387.2	18	MANE Select
NM_001242786.2	RefSeq	NP_001229715.1	16	Standard
NM_001242787.2	RefSeq	NP_001229716.1	16	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
brf1a	Danio rerio	Structure: thrombocyte Quality: decreased amount abnormal

Gene / Model

Organism

Observed Phenotype

brf1a

Danio rerio

Structure: thrombocyte

Quality: decreased amount

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Gene expression (Transcription)
rna polymerase iii transcription
RNA Polymerase III Abortive And Retractive Initiation
RNA Polymerase III Transcription Initiation From Type 1 Promoter
RNA Polymerase III Transcription Initiation From Type 2 Promoter

Biological Process

DNA-templated transcription, initiation
transcription by RNA polymerase III
transcription initiation from RNA polymerase III promoter
rRNA transcription
tRNA transcription

Molecular Function

RNA polymerase III general transcription initiation factor activity
RNA polymerase III type 3 promoter sequence-specific DNA binding
transcription factor binding
TBP-class protein binding
metal ion binding

Cellular Component

transcription factor TFIIIB complex
nucleus
nucleoplasm

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000546474
Coding exons: 18
Length: 106304
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	0.139	421	429	0.981	0.0000280	4406
Missense (PolyPhen)		104	124.06	0.83829		1242
Synonymous	-3.94	264	194	1.36	0.0000146	1349
Loss of Function	3.38	13	34.4	0.378	0.00000165	405

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000062	0.000062	rare
Latino/Admixed American	0.00017	0.00017	rare
Ashkenazi Jewish	0.00020	0.00020	rare
East Asian	0.000054	0.000054	rare
Finnish	0.000094	0.000092	rare
European (Non-Finnish)	0.00012	0.00012	rare
South Asian	0.000065	0.000065	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: 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.;
Disease: DISEASE: 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. {ECO:0000269|PubMed:25561519}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Intolerance Scores

LoFtool: 0.0422
RVIS EVS: -2.06
RVIS percentile EVS: 1.62

Essentials

Essential (CRISPR): E
Essential (CRISPR2): E
Essential (gene trap): E
Indispensability pred.: E
Indispensability score: 1.00

Gene Damage Prediction

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