POLRMT

protein-coding

RNA polymerase mitochondrial, the group of Pentatricopeptide repeat containing

Gene summary

This gene encodes a mitochondrial DNA-directed RNA polymerase. The gene product is responsible for mitochondrial gene expression as well as for providing RNA primers for initiation of replication of the mitochondrial genome. Although this polypeptide has the same function as the three nuclear DNA-directed RNA polymerases, it is more closely related to RNA polymerases of phage and mitochondrial polymerases of lower eukaryotes. [provided by RefSeq, Jul 2008]

MANE transcript

NM_005035.4

Inheritance

AR, AD

ClinVar variants

P:25U:380B:91

Top phenotype

Combined oxidative phosphorylation deficiency 55

gnomAD constraint

pLI —, LoF o/e 0.72

Max pathogenic AF

—

Genomic locus

chr19:617,221-633,537

External References & Databases

Ensembl (ENSG00000099821)

Transcript & Mutation Effects

hg38 • Region Span ~16.3 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

combined oxidative phosphorylation deficiency 55LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0859228

Submitter: Ambry Genetics

combined oxidative phosphorylation deficiency 55MODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0859228

Submitter: PanelApp Australia

combined oxidative phosphorylation deficiency 55LIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0859228

Submitter: Ambry Genetics

combined oxidative phosphorylation deficiency 55STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0859228

Submitter: Labcorp Genetics (formerly Invitae)

combined oxidative phosphorylation deficiency 55LIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0859228

Submitter: Labcorp Genetics (formerly Invitae)

combined oxidative phosphorylation deficiency 55STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0859228

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Combined oxidative phosphorylation deficiency 55AD/AR

Manifestation: Biochemical; Musculoskeletal; Neurologic; Renal

Intervention: Biochemical; Renal

Rationale: The condition can involve renal and other manifestations, and medical management for this and other manifestations (eg, with elemental phosphorus, calcitriol, and sodium citrate), has been described as benefiical, including related to musculoskeletal sequelae

Refs: 24386581; 33602924

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to POLRMT variants in ClinVar

8 Conditions Cataloged

not specifiedTotal: 379

not providedTotal: 96

Combined oxidative phosphorylation deficiency 55Total: 73

POLRMT-related disorderTotal: 22

Neurodevelopmental disorderTotal: 1

Autosomal dominant progressive external ophthalmoplegiaTotal: 1

Progressive sclerosing poliodystrophyTotal: 1

Long QT syndromeTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_005035.4. 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.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			3 clinvar	42 clinvar	2 clinvar	47
missense	6 clinvar	2 clinvar	367 clinvar	43 clinvar	4 clinvar	422
nonsense	1 clinvar	6 clinvar	3 clinvar			10
start loss						0
frameshift	2 clinvar	6 clinvar	1 clinvar			9
splice donor/acceptor (+/-2bp)		2 clinvar	6 clinvar			8
Total	9	16	380	85	6	496

Highest pathogenic variant AF is 0.000699868

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 103 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_005035.4	RefSeq	NP_005026.3	21	MANE Select
ENST00000588649.7	Ensembl	ENSP00000465759.2	21	MANE Select
NM_001407805.1	RefSeq	NP_001394734.1	21	Standard
NM_001407806.1	RefSeq	NP_001394735.1	21	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Mitochondrial biogenesis
Mitochondrial Gene Expression
Gene expression (Transcription)
Purine metabolism
Pyrimidine metabolism

Biological Process

mitochondrial transcription
transcription initiation from mitochondrial promoter
mitochondrion organization

Molecular Function

mitochondrial promoter sequence-specific DNA binding
RNA binding
DNA-directed 5'-3' RNA polymerase activity
protein binding
sequence-specific DNA binding

Cellular Component

mitochondrion
mitochondrial matrix
protein-containing complex
mitochondrial DNA-directed RNA polymerase complex
mitochondrial nucleoid

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000588649
Coding exons: 21
Length: 16375
Individuals with no LoFs: 125625
Homozygous LoFs: 0
Heterozygous LoFs: 108
Defined: 125733
p: 0.000430

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-1.87	933	786	1.19	0.0000567	7758
Missense (PolyPhen)		301	275.09	1.0942		2690
Synonymous	-8.07	550	356	1.54	0.0000267	2512
Loss of Function	1.89	39	54.0	0.722	0.00000248	601

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00045	0.00043	rare
Latino/Admixed American	0.00018	0.00017	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00050	0.00049	rare
Finnish	0.00013	0.000092	rare
European (Non-Finnish)	0.00043	0.00040	rare
South Asian	0.0012	0.0012	notable
Other	0.00034	0.00033	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: DNA-dependent RNA polymerase catalyzes the transcription of mitochondrial DNA into RNA using the four ribonucleoside triphosphates as substrates. {ECO:0000269|PubMed:21278163}.;

Recessive Scores

pRec: 0.113

Intolerance Scores

LoFtool: 0.770
RVIS EVS: -0.02
RVIS percentile EVS: 51.92

Essentials

Essential (CRISPR): N
Essential (CRISPR2): E
Essential (gene trap): K
Indispensability pred.: E
Indispensability score: 0.847

Gene Damage Prediction

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