POLR3B
protein-codingRNA polymerase III subunit B, the group of RNA polymerase subunits
Gene summary
This gene encodes the second largest subunit of RNA polymerase III, the polymerase responsible for synthesizing transfer and small ribosomal RNAs in eukaryotes. The largest subunit and the encoded protein form the catalytic center of RNA polymerase III. Mutations in this gene are a cause of hypomyelinating leukodystrophy. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Dec 2011]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~152.5 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0700092
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0030677
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0019505
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0013722
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0013722
Submitter: Illumina
Inheritance Pattern: AD
Disease ID:MONDO:0700277
Submitter: ClinGen
Heterozygous POLR3B variants were first reported in association with neurologic disease in 2021 (Djordjevic et al., PMID: 33417887). Reported phenotypes include ataxia, spasticity, and demyelinating neuropathy (Djordjevic et al., PMID: 33417887). Prior to this report, many patients were clinically diagnosed with Charcot-Marie-Tooth. Biallelic POLR3B variants were first reported in relation to hypomyelinating leukodystrophy, with or without motor dysfunction, progressive cerebellar dysfunction, dystonia, spasticity, cognitive dysfunction, abnormal dentition, short stature (with or without growth hormone deficiency, hypogonadotropic gonadism, and ocular abnormalities (Saitsu et al., PMID: 22036171). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in inheritance pattern, phenotypic variability, with proposed differences in molecular mechanism. Therefore, the following disease entities have been split into multiple disease entities: autosomal dominant POLR3B-related disorder (including Charcot-Marie-Tooth disease demyelinating, type 1I, OMIM:619742) and autosomal recessive POLR3B-related disorder (Leukodystrophy, hypomyelinating, 8 with or without oligodontia and/or hypogonadotropic hypogonadism OMIM:614381). The latter was previously curated and reached definitive classification The curation for autosomal dominant POLR3B-related disorder includes 21 missense variants that have been reported in 23 probands in 8 publications (PMIDs: 33417887, 34666706, 38002527, 39178560, 35482004, 37897416, 37776383, 39348199) are included in this curation. The maximum score of 12 for genetic evidence was reached. The mechanism of pathogenicity is suggested to be dominant negative due to being “potentially capable of altering the assembly of the functionally active polymerase III pre-initiation complex” (Colona et al., PMID: 38002527, Abasacal-Palacios, et al., PMID: 2934563). De novo POLR3B variants affect the assembly of specific RNA polymerase III subunits (Djordjevic et al., PMID: 33417887). There are no mouse models available for autosomal dominant POLR3B-related disorder. In summary, there is definitive evidence supporting the relationship between POLR3B and autosomal dominant POLR3B-related disorder. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen Leukodystrophy and Leukoencephalopathy GCEP on the meeting date April 16, 2025 (SOP Version 11).
Inheritance Pattern: AR
Disease ID:MONDO:0700277
Submitter: ClinGen
Biallelic POLR3B variants were first reported in association to neurologic disease in 2011 (Saitsu et al., PMID: 22036171). Reported phenotypes include hypomyelinating leukodystrophy, with or without motor dysfunction, progressive cerebellar dysfunction, dystonia, spasticity, cognitive dysfunction, abnormal dentition, short stature (with or without growth hormone deficiency, hypogonadotropic gonadism, and ocular abnormalities (Bernard et al., PMID: 22855961). Prior to this report, the first report of cerebellar hypoplasia with endosteal sclerosis was described in 1986 (Stoll et al. PMID: 3729252). Heterozygous POLR3B variants were first reported in association with neurologic disease in 2021. Reported phenotypes include ataxia, spasticity, and demyelinating neuropathy (Djordjevic et al., PMID: 33417887). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in inheritance pattern, phenotypic variability, with proposed differences in molecular mechanism. Therefore, the following disease entities have been split into multiple disease entities, autosomal dominant POLR3B-related disorder (Charcot-Marie-Tooth disease demyelinating, type 1I, OMIM:619742) and autosomal recessive POLR3B-related disorder (Leukodystrophy, hypomyelinating, 8 with or without oligodontia and/or hypogonadotropic hypogonadism OMIM:614381). 16 variants (missense, splice site, nonsense, frameshift) that have been reported in 9 probands in 7 publications (PMIDs: 22036171, 22036172, 35434302,36650939, 27512013, 30548255, 31577365) are included in this curation. More evidence is available in the literature, and a maximum score of 12 for genetic evidence has been reached (max 12). The mechanism of pathogenicity is reported to be loss of function (Saitsu et al., PMID: 22036171). This gene-disease relationship is also supported by both zebrafish and mouse models (PMIDs: 37635302, 36650939). In summary, there is definitive evidence supporting the relationship between POLR3B and autosomal recessive POLR3B-related disorder. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen Leukodystrophy and Leukoencephalopathy GCEP on the meeting date February 24, 2025 (SOP Version 11).
Inheritance Pattern: AD
Disease ID:MONDO:0030677
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0013722
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0013722
Submitter: PanelApp Australia
Clinical Genomic Database (CGD)
Manifestation: Dental; Endocrine; 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
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to POLR3B variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_018082.6. 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 | 14 | 107 | 121 | |||
| missense | 10 | 39 | 360 | 6 | 415 | |
| nonsense | 2 | 12 | 5 | 19 | ||
| start loss | 0 | |||||
| frameshift | 9 | 11 | 4 | 1 | 25 | |
| splice donor/acceptor (+/-2bp) | 2 | 19 | 14 | 35 | ||
| Total | 23 | 81 | 397 | 114 | 0 | 615 |
Highest pathogenic variant AF is 0.0008712399
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_060552.4 | 28 | MANE Select | |
| Ensembl | ENSP00000228347.4 | 28 | MANE Select | |
| RefSeq | NP_001154180.1 | 25 | Standard | |
| Ensembl | ENSP00000445721.1 | 25 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| polr3b | Danio rerio | Structure: exocrine cell Quality: undifferentiated abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Pyrimidine metabolism - Homo sapiens (human)
- Cytosolic DNA-sensing pathway - Homo sapiens (human)
- RNA polymerase - Homo sapiens (human)
- Purine metabolism - Homo sapiens (human)
- Epstein-Barr virus infection - Homo sapiens (human)
Biological Process
- transcription by RNA polymerase III
- positive regulation of interferon-beta production
- innate immune response
- positive regulation of innate immune response
- defense response to virus
Molecular Function
- RNA polymerase III activity
- DNA binding
- DNA-directed 5'-3' RNA polymerase activity
- ribonucleoside binding
- metal ion binding
Cellular Component
- nucleoplasm
- RNA polymerase III complex
- cytosol
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000228347
- Coding exons
- 28
- Length
- 152541
- Individuals with no LoFs
- 125630
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 118
- Defined
- 125748
- p
- 0.000469
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 3.20 | 402 | 627 | 0.641 | 0.0000348 | 7453 |
| Missense (PolyPhen) | 95 | 231.85 | 0.40974 | 2636 | ||
| Synonymous | 0.802 | 206 | 221 | 0.931 | 0.0000125 | 2118 |
| Loss of Function | 2.46 | 47 | 69.0 | 0.681 | 0.00000430 | 784 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00031 | 0.00031 | rare |
| Latino/Admixed American | 0.00052 | 0.00052 | rare |
| Ashkenazi Jewish | 0.00099 | 0.00099 | rare |
| East Asian | 0.00076 | 0.00076 | rare |
| Finnish | 0.00014 | 0.00014 | rare |
| European (Non-Finnish) | 0.00043 | 0.00043 | rare |
| South Asian | 0.00059 | 0.00059 | rare |
| Other | 0.00016 | 0.00016 | rare |
dbNSFP Gene Annotations
Source:
- 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 III which synthesizes small RNAs, such as 5S rRNA and tRNAs. Proposed to contribute to the polymerase catalytic activity and forms the polymerase active center together with the largest subunit. Pol III is composed of mobile elements and RPC2 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). Plays a key role in sensing and limiting infection by intracellular bacteria and DNA viruses. Acts as nuclear and cytosolic DNA sensor involved in innate immune response. Can sense non-self dsDNA that serves as template for transcription into dsRNA. The non-self RNA polymerase III transcripts, such as Epstein-Barr virus-encoded RNAs (EBERs) induce type I interferon and NF- Kappa-B through the RIG-I pathway. {ECO:0000250, ECO:0000269|PubMed:19609254, ECO:0000269|PubMed:19631370}.;
- Disease
- DISEASE: Leukodystrophy, hypomyelinating, 8, with or without oligodontia and/or hypogonadotropic hypogonadism (HLD8) [MIM:614381]: An autosomal recessive neurodegenerative disorder characterized by early childhood onset of cerebellar ataxia and mild intellectual disabilities associated with diffuse hypomyelination apparent on brain MRI. Variable features include oligodontia and/or hypogonadotropic hypogonadism. {ECO:0000269|PubMed:22036171, ECO:0000269|PubMed:22036172, ECO:0000269|PubMed:23355746}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.130
Intolerance Scores
- LoFtool
- 0.956
- RVIS EVS
- -1.48
- RVIS percentile EVS
- 3.66
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- E
- Essential (gene trap)
- E
- Indispensability pred.
- E
- Indispensability score
- 0.813
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |