POLR1A

protein-coding

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

Gene summary

The protein encoded by this gene is the largest subunit of the RNA polymerase I complex. The encoded protein represents the catalytic subunit of the complex, which transcribes DNA into ribosomal RNA precursors. Defects in this gene are a cause of the Cincinnati type of acrofacial dysostosis. [provided by RefSeq, May 2016]

MANE transcript

NM_015425.6

Inheritance

AD, AR

ClinVar variants

P:12U:622B:323

Top phenotype

Acrofacial dysostosis, Cincinnati type; Leukodystrophy, hypomyelinating, 27

gnomAD constraint

pLI —, LoF o/e 0.17

Max pathogenic AF

—

Genomic locus

chr2:86,020,216-86,106,155

External References & Databases

Ensembl (ENSG00000068654)

Transcript & Mutation Effects

hg38 • Region Span ~85.9 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

acrofacial dysostosis Cincinnati typeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014651

Submitter: PanelApp Australia

leukodystrophy, hypomyelinating, 27MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0958018

Submitter: PanelApp Australia

choanal atresia-hearing loss-cardiac defects-craniofacial dysmorphism syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012064

Submitter: Orphanet

acrofacial dysostosis Cincinnati typeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014651

Submitter: Labcorp Genetics (formerly Invitae)

acrofacial dysostosis Cincinnati typeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014651

Submitter: G2P

acrofacial dysostosis Cincinnati typeMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0014651

Submitter: Ambry Genetics

leukodystrophy, hypomyelinating, 27LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0958018

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Acrofacial dysostosis, Cincinnati type; Leukodystrophy, hypomyelinating, 27AD/AR

Manifestation: Craniofacial; 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: 25913037; 28051070; 36917474

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to POLR1A variants in ClinVar

9 Conditions Cataloged

not providedTotal: 987

Inborn genetic diseasesTotal: 222

not specifiedTotal: 79

Acrofacial dysostosis Cincinnati typeTotal: 47

POLR1A-related disorderTotal: 31

Leukodystrophy, hypomyelinating, 27Total: 20

Intellectual disability, autosomal dominant 9Total: 1

Multiple congenital anomalies/dysmorphic syndromeTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_015425.6. 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			8 clinvar	276 clinvar	9 clinvar	293
missense	2 clinvar	2 clinvar	581 clinvar	31 clinvar	7 clinvar	623
nonsense	1 clinvar	2 clinvar	14 clinvar			17
start loss						0
frameshift	1 clinvar	4 clinvar	6 clinvar			11
splice donor/acceptor (+/-2bp)			13 clinvar			13
Total	4	8	622	307	16	957

Highest pathogenic variant AF is 0.0000054772913

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 10 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_015425.6	RefSeq	NP_056240.2	34	MANE Select
ENST00000263857.11	Ensembl	ENSP00000263857.6	34	MANE Select
ENST00000409024.3	Ensembl	ENSP00000386423.3	2	Standard
ENST00000409681.1	Ensembl	ENSP00000386300.1	34	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
polr1a	Danio rerio	Structure: melanocyte Quality: quality abnormal

Gene / Model

Organism

Observed Phenotype

polr1a

Danio rerio

Structure: melanocyte

Quality: quality

abnormal

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)
Nucleotide Excision Repair
Pyrimidine metabolism

Biological Process

transcription initiation from RNA polymerase I promoter
termination of RNA polymerase I transcription
positive regulation of gene expression, epigenetic
negative regulation of protein localization to nucleolus

Molecular Function

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

Cellular Component

nucleoplasm
RNA polymerase I complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000263857
Coding exons: 34
Length: 85940
Individuals with no LoFs: 124765
Homozygous LoFs: 0
Heterozygous LoFs: 49
Defined: 124814
p: 0.000196

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.95	750	1.01e+3	0.739	0.0000612	11278
Missense (PolyPhen)		268	497.29	0.53892		5537
Synonymous	1.03	394	421	0.936	0.0000277	3345
Loss of Function	7.50	16	94.8	0.169	0.00000546	1027

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00013	0.00013	rare
Latino/Admixed American	0.00036	0.00035	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00017	0.00017	rare
Finnish	0.00023	0.00023	rare
European (Non-Finnish)	0.00013	0.00013	rare
South Asian	0.00039	0.00039	rare
Other	0	0.0	absent

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 I which synthesizes ribosomal RNA precursors. 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 I. A bridging helix emanates from RPA1 and crosses the cleft near the catalytic site and is thought to promote translocation of Pol I 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). {ECO:0000250|UniProtKB:P10964}.;
Disease: DISEASE: Acrofacial dysostosis, Cincinnati type (AFDCIN) [MIM:616462]: A form of acrofacial dysostosis, a group of disorders which are characterized by malformation of the craniofacial skeleton and, in some patients, the limbs. {ECO:0000269|PubMed:25913037}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.220

Intolerance Scores

LoFtool: 0.404
RVIS EVS: 0.09
RVIS percentile EVS: 60.33

Essentials

Essential (CRISPR): E
Essential (CRISPR2): E
Essential (gene trap): E
Indispensability pred.: N
Indispensability score: 0.379

Gene Damage Prediction

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