GeneBe

POLR1D

protein-coding

RNA polymerase I and III subunit D, the group of RNA polymerase subunits

Gene summary

The protein encoded by this gene is a component of the RNA polymerase I and RNA polymerase III complexes, which function in the synthesis of ribosomal RNA precursors and small RNAs, respectively. Mutations in this gene are a cause of Treacher Collins syndrome (TCS), a craniofacial development disorder. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Apr 2011]

MANE transcript

NM_015972.4

Inheritance

AD, AR

ClinVar variants

P:25U:65B:10

Top phenotype

Treacher Collins syndrome 2

gnomAD constraint

pLI —, LoF o/e 0.21

Max pathogenic AF

—

Genomic locus

chr13:27,620,742-27,744,237

External References & Databases

Ensembl (ENSG00000186184)NCBI Gene (51082)OMIM (613715)HGNC:20422GenCCUniProt (P0DPB5, P0DPB6)AlphaFoldClinVar (POLR1D)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~123.5 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Treacher Collins syndrome 2DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0013385

Submitter: G2P

Treacher Collins syndrome 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013385

Submitter: PanelApp Australia

Treacher-Collins syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0002457

Submitter: Orphanet

Treacher-Collins syndromeLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0002457

Submitter: Ambry Genetics

Treacher Collins syndrome 2DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0013385

Submitter: ClinGen

POLR1D has been repeatedly described in association with autosomal dominant Treacher Collins Syndrome 2 (TCS2). TCS2 is a disorder of craniofacial development characterized by downward slanting palpebral fissures, coloboma, hypoplasia of the facial bones, cleft palate, malformation of the external ears, and bilateral conductive hearing loss. At least 3 missense and 5 nonsense variants have been reported in at least 10 probands from 5 publications (PMIDs: 21131976, 25790162, 31107123, 34397304, 34136434). In addition to these variants, there has been one missense variant (p.Leu55Val) determined to have an autosomal recessive mode of inheritance in three unrelated probands (PMIDs: 24603435, 25790162). However, this information was not scored for autosomal dominant TCS2. This gene disease association is also supported by experimental evidence including protein interactions and an animal model (PMIDs: 8955128, 27448281). In summary, POLR1D is definitively associated with autosomal dominant Treacher Collins Syndrome 2. 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 Craniofacial Malformations Gene Curation Expert Panel on 12/15/2022. (SOP Version 9)

Treacher Collins syndrome 2STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0013385

Submitter: Labcorp Genetics (formerly Invitae)

Treacher Collins syndrome 2STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0013385

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Treacher Collins syndrome 2AD/AR

Manifestation: Audiologic/Otolaryngologic; Craniofacial; Dental

Intervention: Audiologic/Otolaryngologic

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

Refs: 21131976; 24603435; 25790162Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to POLR1D variants in ClinVar

7 Conditions Cataloged
not providedTotal: 66
Treacher Collins syndrome 2Total: 20
POLR1D-related disorderTotal: 18
Inborn genetic diseasesTotal: 18
not specifiedTotal: 6
Treacher Collins syndromeTotal: 1
Hearing impairmentTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_015972.4. 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
8
clinvar
1
clinvar
 9
missense
2
clinvar
3
clinvar
57
clinvar
1
clinvar
 63
nonsense
1
clinvar
3
clinvar
3
clinvar
 7
start loss
1
clinvar
 1
frameshift
7
clinvar
8
clinvar
2
clinvar
 17
splice donor/acceptor (+/-2bp)
1
clinvar
2
clinvar
 3
Total10156591100

Highest pathogenic variant AF is 0.0000013681406

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 30 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_015972.4RefSeqNP_057056.12MANE Select
ENST00000302979.5EnsemblENSP00000302478.42MANE Select
NM_001206559.2RefSeqNP_001193488.12Standard
NM_001374407.1RefSeqNP_001361336.12Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / ModelOrganismObserved Phenotype
polr1dDanio rerio

Structure: neuroepithelial cell

Quality: apoptotic

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, DNA-templated

Molecular Function

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

Cellular Component

  • RNA polymerase III complex
  • RNA polymerase I complex

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000302979
Coding exons
2
Length
46646
Individuals with no LoFs
125744
Homozygous LoFs
0
Heterozygous LoFs
1
Defined
125745
p
0.00000398
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense0.1697074.10.9450.00000396880
Missense (PolyPhen)1519.1660.78263252
Synonymous0.9872127.60.7610.00000153245
Loss of Function1.5714.660.2142.62e-758

Population LoF Frequency

PopulationCAFp-valueStatus
African00.0absent
Latino/Admixed American00.0absent
Ashkenazi Jewish00.0absent
East Asian00.0absent
Finnish0.0000460.000046rare
European (Non-Finnish)00.0absent
South Asian00.0absent
Other00.0absent

dbNSFP Gene Annotations

Source: dbNSFP

Recessive Scores

pRec
0.163

Intolerance Scores

LoFtool
0.245
RVIS EVS
-0.32
RVIS percentile EVS
31.69

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
S
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.909

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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