TOP3A

protein-coding

DNA topoisomerase III alpha, the group of Topoisomerases|Zinc fingers GRF-type

Gene summary

This gene encodes a DNA topoisomerase, an enzyme that controls and alters the topologic states of DNA during transcription. This enzyme catalyzes the transient breaking and rejoining of a single strand of DNA which allows the strands to pass through one another, thus reducing the number of supercoils and altering the topology of DNA. This enzyme forms a complex with BLM which functions in the regulation of recombination in somatic cells. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Mar 2016]

Previous symbols:

TOP3

MANE transcript

NM_004618.5

Inheritance

ClinVar variants

P:44U:216B:160

Top phenotype

Microcephaly, growth restriction, and increased sister chromatid exchange 2; Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 5

gnomAD constraint

pLI —, LoF o/e 0.49

Max pathogenic AF

—

Genomic locus

chr17:18,271,428-18,315,007

External References & Databases

Ensembl (ENSG00000177302)

Transcript & Mutation Effects

hg38 • Region Span ~43.6 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

microcephaly, growth restriction, and increased sister chromatid exchange 2DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0020628

Submitter: Ambry Genetics

microcephaly, growth restriction, and increased sister chromatid exchange 2DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0020628

Submitter: G2P

microcephaly, growth restriction, and increased sister chromatid exchange 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0020628

Submitter: PanelApp Australia

progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 5LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0020845

Submitter: PanelApp Australia

progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 5STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0020845

Submitter: Labcorp Genetics (formerly Invitae)

microcephaly, growth restriction, and increased sister chromatid exchange 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0020628

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Microcephaly, growth restriction, and increased sister chromatid exchange 2; Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 5AR

Manifestation: Allergy/Immunology/Infectious; Audiologic/Otolaryngologic; Cardiovascular; Craniofacial; Dermatologic; Musculoskeletal; Neurologic

Intervention: Allergy/Immunology/Infectious; Cardiovascular

Rationale: In Microcephaly, growth restriction, and increased sister chromatid exchange 2, the condition can include frequent infections, and awareness may allow early and aggressive treatment of infections; Individuals have been described with cardiomyopathy, and awareness may allow surveillance and prompt management; In Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 5, the condition may involve cardiac dysfunction, and awareness may allow early detection and management

Refs: 29290614; 30057030

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TOP3A variants in ClinVar

10 Conditions Cataloged

not providedTotal: 379

Inborn genetic diseasesTotal: 135

TOP3A-related disorderTotal: 44

not specifiedTotal: 34

Microcephaly, growth restriction, and increased sister chromatid exchange 2Total: 17

Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 5Total: 14

Monogenic short statueTotal: 2

Mitochondrial diseaseTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_004618.5. 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			1 clinvar	132 clinvar	4 clinvar	137
missense	2 clinvar	3 clinvar	202 clinvar	19 clinvar	5 clinvar	231
nonsense	6 clinvar	6 clinvar	1 clinvar			13
start loss			2 clinvar			2
frameshift	12 clinvar	7 clinvar	4 clinvar			23
splice donor/acceptor (+/-2bp)	1 clinvar	7 clinvar	6 clinvar			14
Total	21	23	216	151	9	420

Highest pathogenic variant AF is 0.00008488754

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 33 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_004618.5	RefSeq	NP_004609.1	19	MANE Select
ENST00000321105.10	Ensembl	ENSP00000321636.5	19	MANE Select
NM_001320759.2	RefSeq	NP_001307688.1	17	Standard
ENST00000461127.5	Ensembl	ENSP00000464338.1	4	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
top3a	Danio rerio	Structure: T cell Quality: decreased amount abnormal

Gene / Model

Organism

Observed Phenotype

top3a

Danio rerio

Structure: T cell

Quality: decreased amount

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Fanconi anemia pathway - Homo sapiens (human)
Homologous recombination - Homo sapiens (human)
HDR through Single Strand Annealing (SSA)
HDR through Homologous Recombination (HR) or Single Strand Annealing (SSA)
DNA Repair

Biological Process

DNA replication
DNA topological change
mitochondrial DNA metabolic process
chromosome separation
meiotic cell cycle

Molecular Function

DNA binding
single-stranded DNA binding
DNA topoisomerase activity
DNA topoisomerase type I activity
protein binding

Cellular Component

nucleus
nucleoplasm
chromosome
mitochondrion
PML body

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000321105
Coding exons: 19
Length: 43580
Individuals with no LoFs: 125580
Homozygous LoFs: 1
Heterozygous LoFs: 167
Defined: 125748
p: 0.000668

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.31	493	582	0.847	0.0000327	6548
Missense (PolyPhen)		158	222.98	0.70858		2456
Synonymous	-1.08	248	227	1.09	0.0000132	1963
Loss of Function	3.42	26	52.8	0.492	0.00000299	565

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00019	0.00018	rare
Latino/Admixed American	0.00038	0.00038	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0.00028	0.00027	rare
Finnish	0.00032	0.00032	rare
European (Non-Finnish)	0.00058	0.00058	rare
South Asian	0.0024	0.0023	notable
Other	0.00033	0.00033	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Releases the supercoiling and torsional tension of DNA introduced during the DNA replication and transcription 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-(5'-phosphotyrosyl)-enzyme intermediate and the expulsion of a 3'-OH DNA strand. The free DNA strand then undergoes passage around the unbroken strand thus removing DNA supercoils. Finally, in the religation step, the DNA 3'-OH attacks the covalent intermediate to expel the active-site tyrosine and restore the DNA phosphodiester backbone. Essential component of the RMI complex, a complex that plays an important role in the processing of homologous recombination intermediates to limit DNA crossover formation in cells. Has DNA decatenation activity. {ECO:0000269|PubMed:20445207, ECO:0000269|PubMed:8622991}.;

Recessive Scores

pRec: 0.0939

Intolerance Scores

LoFtool: 0.856
RVIS EVS: 0.3
RVIS percentile EVS: 71.7

Essentials

Essential (CRISPR): E
Essential (CRISPR2): E
Essential (gene trap): E
Indispensability pred.: E
Indispensability score: 0.731

Gene Damage Prediction

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