TOP1MT

protein-coding

DNA topoisomerase I mitochondrial, the group of Topoisomerases

Gene summary

This gene encodes a mitochondrial DNA topoisomerase that plays a role in the modification of DNA topology. The encoded protein is a type IB topoisomerase and catalyzes the transient breaking and rejoining of DNA to relieve tension and DNA supercoiling generated in the mitochondrial genome during replication and transcription. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, May 2012]

MANE transcript

NM_052963.3

Inheritance

—

ClinVar variants

U:185B:78

Top phenotype

Premature ovarian insufficiency

gnomAD constraint

pLI —, LoF o/e 1.31

Max pathogenic AF

—

Genomic locus

chr8:143,304,384-143,359,979

External References & Databases

Ensembl (ENSG00000184428)

Transcript & Mutation Effects

hg38 • Region Span ~55.6 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

No GenCC data available for this gene.

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TOP1MT variants in ClinVar

4 Conditions Cataloged

not providedTotal: 227

not specifiedTotal: 109

Premature ovarian insufficiencyTotal: 1

Sensorineural hearing loss disorderTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_052963.3. 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			6 clinvar	49 clinvar	6 clinvar	61
missense			161 clinvar	15 clinvar	8 clinvar	184
nonsense			8 clinvar			8
start loss						0
frameshift			5 clinvar			5
splice donor/acceptor (+/-2bp)			5 clinvar			5
Total	0	0	185	64	14	263

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 62 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_052963.3	RefSeq	NP_443195.1	14	MANE Select
ENST00000329245.9	Ensembl	ENSP00000328835.3	14	MANE Select
NM_001258446.1	RefSeq	NP_001245375.1	12	Standard
NM_001258447.1	RefSeq	NP_001245376.1	12	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

DNA replication
DNA topological change

Molecular Function

DNA binding
DNA topoisomerase type I activity

Cellular Component

nucleus
chromosome
mitochondrion
mitochondrial nucleoid

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000329245
Coding exons: 14
Length: 55596
Individuals with no LoFs: 125367
Homozygous LoFs: 0
Heterozygous LoFs: 381
Defined: 125748
p: 0.00152

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.109	393	387	1.02	0.0000255	3914
Missense (PolyPhen)		146	135.24	1.0796		1548
Synonymous	0.134	163	165	0.987	0.0000120	1143
Loss of Function	-1.70	45	34.3	1.31	0.00000197	368

Population LoF Frequency

Population	CAF	p-value	Status
African	0.0022	0.0022	notable
Latino/Admixed American	0.0018	0.0018	notable
Ashkenazi Jewish	0.0021	0.0021	notable
East Asian	0.0019	0.0019	notable
Finnish	0.00079	0.00079	rare
European (Non-Finnish)	0.0014	0.0014	notable
South Asian	0.0016	0.0016	notable
Other	0.0015	0.0015	notable

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Releases the supercoiling and torsional tension of DNA introduced during duplication of mitochondrial DNA by transiently cleaving and rejoining one strand of the DNA duplex. Introduces a single-strand break via transesterification at a target site in duplex DNA. The scissile phosphodiester is attacked by the catalytic tyrosine of the enzyme, resulting in the formation of a DNA-(3'-phosphotyrosyl)-enzyme intermediate and the expulsion of a 5'-OH DNA strand. The free DNA strand then rotates around the intact phosphodiester bond on the opposing strand, thus removing DNA supercoils. Finally, in the religation step, the DNA 5'-OH attacks the covalent intermediate to expel the active-site tyrosine and restore the DNA phosphodiester backbone (By similarity). {ECO:0000250, ECO:0000269|PubMed:11526219}.;

Recessive Scores

pRec: 0.148

Intolerance Scores

LoFtool: 0.985
RVIS EVS: -0.44
RVIS percentile EVS: 24.71

Essentials

Essential (CRISPR): E
Essential (CRISPR2): S
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.190

Gene Damage Prediction

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