GeneBe

POLR3A

protein-coding

RNA polymerase III subunit A, the group of RNA polymerase subunits

Gene summary

The protein encoded by this gene is the catalytic component of RNA polymerase III, which synthesizes small RNAs. The encoded protein also acts as a sensor to detect foreign DNA and trigger an innate immune response. [provided by RefSeq, Aug 2011]

MANE transcript

NM_007055.4

Inheritance

AR, AD

ClinVar variants

P:167U:446B:314

Top phenotype

Leukodystrophy, hypomyelinating, 7, with or without oligodontia and/or hypogonadotropic hypogonadism; Wiedemann-Rautenstrauch syndrome

gnomAD constraint

pLI —, LoF o/e 0.69

Max pathogenic AF

—

Genomic locus

chr10:77,953,148-78,029,522

External References & Databases

Ensembl (ENSG00000148606)NCBI Gene (11128)OMIM (614258)HGNC:30074GenCCUniProt (O14802)AlphaFoldClinVar (POLR3A)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~76.4 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

POLR3A-related disorderDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0700276

Submitter: ClinGen

The association of POLR3A variants with autosomal recessive tremor-ataxia with central hypomyelination (TACH), leukodystrophy with oligodontia (LO), and hypomyelination, hypodontia and hypogonadotropic hypogonadism (4H) syndrome was first described in 2011 (Bernard, et al. 2011, PMID: 21855841). Variants were then described in association with Wiedemann-Rautenstrauch syndrome (WRS) (PMID: 30414627) in 2018. Per criteria outlined by the Clingen Lumping and Splitting Working Group, we found no difference in molecular mechanism(s) or inheritance pattern; and found that the spectrum of phenotypic variability could exist between the described disease entities. Therefore, the prior disease entities have been lumped into one entity, POLR3A-Related Disorders (MONDO:0700276). Clinical characteristics include a variable age of onset with a spectrum of global developmental delay, failure to thrive, hypomyelinating leukodystrophy, neurological dysfunction, dental abnormalities, and hypogonadotropic hypogonadism. POLR3A is the largest subunit of RNA Polymerase III, which transcribes ribosomal, transfer, and nuclear RNAs (PMID: 34395528). Included in this curation are twelve unique variants found in nine subjects across four publications. Four of the twelve variants are predicted or proven null variants (canonical splice site variants or nonsense), the remainder are missense variants. Four of the variants had functional data supporting pathogenicity of the variant (PMID: 21855841, PMID: 30898877, PMID:38561452). Two variants had points upgraded due to variant recurrence across non-related affected patients. The mechanism of function is loss-of-function. Gene-disease relationship is supported by mouse models with POLR3A mutations (PMID: 38168294, PMID: 34583988). The gene-disease pair has had replication over time showing convincing evidence. More evidence in the literature is present, but the maximum score required for genetic evidence has been reached (12 points). To summarize, there is definitive evidence supporting the relationship between POLR3A and POLR3A-Related Disorders, with rigorous and reproducible evidence in clinical and research settings. This gene-disease curation based on ClinGen criteria was approved by the Leukodystrophy and Leukoencephalopathy GCEP on 8/28/2024 (SOP version 10).

POLR3A-related disorderSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0700276

Submitter: PanelApp Australia

varicella zoster infectionMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0005608

Submitter: PanelApp Australia

leukodystrophy, hypomyelinating, 7, with or without oligodontia and/or hypogonadotropic hypogonadismSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011897

Submitter: Labcorp Genetics (formerly Invitae)

Wiedemann-Rautenstrauch syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009910

Submitter: Orphanet

odontoleukodystrophyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019177

Submitter: Illumina

Wiedemann-Rautenstrauch syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009910

Submitter: Labcorp Genetics (formerly Invitae)

hypomyelination-cerebellar atrophy-hypoplasia of the corpus callosum syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0018655

Submitter: Orphanet

odontoleukodystrophySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019177

Submitter: Orphanet

leukodystrophy, hypomyelinating, 7, with or without oligodontia and/or hypogonadotropic hypogonadismSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011897

Submitter: Orphanet

hypomyelination-hypogonadotropic hypogonadism-hypodontia syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019505

Submitter: Orphanet

tremor-ataxia-central hypomyelination syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0018656

Submitter: Orphanet

Wiedemann-Rautenstrauch syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009910

Submitter: G2P

Clinical Genomic Database (CGD)

Leukodystrophy, hypomyelinating, 7, with or without oligodontia and/or hypogonadotropic hypogonadism; Wiedemann-Rautenstrauch syndromeAR

Manifestation: Craniofacial; Dental; Endocrine; Musculoskeletal; Neurologic; Pulmonary

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: 12605447; 17159124; 20640464; 21855841; 25339210; 27612211; 30323018; 30414627; 30450527Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to POLR3A variants in ClinVar

23 Conditions Cataloged
not providedTotal: 1050
Leukodystrophy, hypomyelinating, 7, with or without oligodontia and/or hypogonadotropic hypogonadismTotal: 234
Inborn genetic diseasesTotal: 125
not specifiedTotal: 115
POLR3A-related disorderTotal: 81
Neonatal pseudo-hydrocephalic progeroid syndromeTotal: 46
LeukodystrophyTotal: 45
POLR-related leukodystrophyTotal: 7

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_007055.4. 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.

EffectPLPVUSLBBSum
synonymous
1
clinvar
15
clinvar
297
clinvar
5
clinvar
 318
missense
3
clinvar
48
clinvar
422
clinvar
12
clinvar
 485
nonsense
22
clinvar
19
clinvar
1
clinvar
 42
start loss
2
clinvar
 2
frameshift
20
clinvar
18
clinvar
2
clinvar
 40
splice donor/acceptor (+/-2bp)
3
clinvar
31
clinvar
6
clinvar
 40
Total481194463095927

Highest pathogenic variant AF is 0.0024086204

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 18 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_007055.4RefSeqNP_008986.231MANE Select
ENST00000372371.8EnsemblENSP00000361446.331MANE Select
ENST00000473588.2EnsemblENSP00000473389.16Standard
ENST00000698731.1EnsemblENSP00000513898.130Standard

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, DNA-templated
  • transcription by RNA polymerase III
  • positive regulation of interferon-beta production
  • innate immune response
  • defense response to virus

Molecular Function

  • RNA polymerase III activity
  • DNA binding
  • chromatin binding
  • DNA-directed 5'-3' RNA polymerase activity
  • metal ion binding

Cellular Component

  • nucleoplasm
  • RNA polymerase III complex
  • cytosol
  • membrane

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000372371
Coding exons
31
Length
54397
Individuals with no LoFs
125603
Homozygous LoFs
0
Heterozygous LoFs
145
Defined
125748
p
0.000577
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense2.315747520.7630.00004429159
Missense (PolyPhen)120246.30.487212910
Synonymous0.5272832950.9610.00001892689
Loss of Function2.404768.40.6870.00000402835

Population LoF Frequency

PopulationCAFp-valueStatus
African0.000620.00062rare
Latino/Admixed American0.000230.00023rare
Ashkenazi Jewish0.0000990.000099rare
East Asian0.000820.00082rare
Finnish0.000140.00014rare
European (Non-Finnish)0.000700.00069rare
South Asian0.000850.00085rare
Other0.000490.00049rare

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. Largest and catalytic core component of RNA polymerase III which synthesizes small RNAs, such as 5S rRNA and tRNAs. Forms the polymerase active center together with the second largest subunit. A single-stranded DNA template strand of the promoter is positioned within the central active site cleft of Pol III. A bridging helix emanates from RPC1 and crosses the cleft near the catalytic site and is thought to promote translocation of Pol III by acting as a ratchet that moves the RNA-DNA hybrid through the active site by switching from straight to bent conformations at each step of nucleotide addition (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}.;

Recessive Scores

pRec
0.122

Intolerance Scores

LoFtool
0.761
RVIS EVS
-1.92
RVIS percentile EVS
1.93

Essentials

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

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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