POLR1B

protein-coding

RNA polymerase I subunit B, the group of RNA polymerase subunits

Gene summary

Eukaryotic RNA polymerase I (pol I) is responsible for the transcription of ribosomal RNA (rRNA) genes and production of rRNA, the primary component of ribosomes. Pol I is a multisubunit enzyme composed of 6 to 14 polypeptides, depending on the species. Most of the mass of the pol I complex derives from the 2 largest subunits, Rpa1 and Rpa2 in yeast. POLR1B is homologous to Rpa2 (Seither and Grummt, 1996 [PubMed 8921381]).[supplied by OMIM, Mar 2008]

MANE transcript

NM_019014.6

Inheritance

ClinVar variants

P:5U:118B:17

Top phenotype

Treacher-Collins syndrome 4

gnomAD constraint

pLI —, LoF o/e 0.12

Max pathogenic AF

—

Genomic locus

chr2:112,541,915-112,579,818

External References & Databases

Ensembl (ENSG00000125630)

Transcript & Mutation Effects

hg38 • Region Span ~37.9 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Treacher Collins syndrome 4MODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0030067

Submitter: ClinGen

*POLR1B* was first reported in relation to autosomal dominant Treacher-Collins syndrome 4 in 2020 (Sanchez et al., PMID: 31649276). Treacher-Collins syndrome 4 is disorder of craniofacial development characterized by craniofacial dysmorphisms including downslanting palpebral fissures, malar and mandibular hypoplasia, and microtia. Most patients have conductive deafness with atretic external ear canals. Choanal atresia and cleft palate have also been observed. At least three missense variants have been reported in six probands in two publications. Though the points scored lead to a limited classification, the expert panel believes there is sufficient evidence to classify missense variants at the position p.Arg1003 as moderate. Evidence supporting this gene-disease relationship includes expression data and animal models (PMID: 31649276). In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the ClinGen Craniofacial Malformations Gene Curation Expert Panel on 2/16/2023. (SOP Version 9)

Treacher Collins syndrome 4STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0030067

Submitter: PanelApp Australia

Treacher Collins syndrome 4LIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0030067

Submitter: Ambry Genetics

Treacher Collins syndrome 4STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0030067

Submitter: Labcorp Genetics (formerly Invitae)

Treacher-Collins syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0002457

Submitter: Orphanet

Clinical Genomic Database (CGD)

Treacher-Collins syndrome 4AD

Manifestation: Audiologic/Otolaryngologic; Craniofacial

Intervention: Audiologic/Otolaryngologic

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

Refs: 31649276

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to POLR1B variants in ClinVar

5 Conditions Cataloged

not specifiedTotal: 108

not providedTotal: 27

Treacher Collins syndrome 4Total: 14

POLR1B-related disorderTotal: 10

Treacher Collins syndromeTotal: 3

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_019014.6. 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				5 clinvar	3 clinvar	8
missense	3 clinvar	1 clinvar	112 clinvar	8 clinvar	1 clinvar	125
nonsense		1 clinvar	2 clinvar			3
start loss						0
frameshift			2 clinvar			2
splice donor/acceptor (+/-2bp)			2 clinvar			2
Total	3	2	118	13	4	140

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 27 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_019014.6	RefSeq	NP_061887.2	15	MANE Select
ENST00000263331.10	Ensembl	ENSP00000263331.5	15	MANE Select
NM_001137604.3	RefSeq	NP_001131076.1	14	Standard
NM_001282772.2	RefSeq	NP_001269701.1	16	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Pyrimidine metabolism - Homo sapiens (human)
RNA polymerase - Homo sapiens (human)
Purine metabolism - Homo sapiens (human)
Pyrimidine metabolism
Eukaryotic Transcription Initiation

Biological Process

transcription initiation from RNA polymerase I promoter
termination of RNA polymerase I transcription
embryo implantation
rRNA transcription
nucleologenesis

Molecular Function

RNA polymerase I activity
DNA binding
DNA-directed 5'-3' RNA polymerase activity
protein binding
ribonucleoside binding

Cellular Component

nucleoplasm
nucleolus
RNA polymerase I complex
cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000263331
Coding exons: 15
Length: 35144
Individuals with no LoFs: 125729
Homozygous LoFs: 0
Heterozygous LoFs: 17
Defined: 125746
p: 0.0000676

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.97	423	634	0.668	0.0000352	7524
Missense (PolyPhen)		79	244.65	0.32291		2782
Synonymous	-0.353	236	229	1.03	0.0000125	2195
Loss of Function	5.63	6	48.1	0.125	0.00000274	579

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00025	0.00025	rare
Latino/Admixed American	0.000029	0.000029	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00011	0.00011	rare
Finnish	0.00014	0.00014	rare
European (Non-Finnish)	0.000053	0.000053	rare
South Asian	0	0.0	absent
Other	0.00018	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: DNA-dependent RNA polymerase catalyzes the transcription of DNA into RNA using the four ribonucleoside triphosphates as substrates. Second largest core component of RNA polymerase I which synthesizes ribosomal RNA precursors. Proposed to contribute to the polymerase catalytic activity and forms the polymerase active center together with the largest subunit. Pol I is composed of mobile elements and RPA2 is part of the core element with the central large cleft and probably a clamp element that moves to open and close the cleft (By similarity). {ECO:0000250}.;

Recessive Scores

pRec: 0.200

Intolerance Scores

LoFtool: 0.566
RVIS EVS: -0.75
RVIS percentile EVS: 13.75

Essentials

Essential (CRISPR): E
Essential (CRISPR2): E
Essential (gene trap): E
Indispensability pred.: E
Indispensability score: 0.860

Gene Damage Prediction

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