TOP3A

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

Basic information

Region (hg38): 17:18271428-18315007

Previous symbols: [ "TOP3" ]

Links

ENSG00000177302 ∙ NCBI:7156 ∙ OMIM:601243 ∙ HGNC:11992 ∙ Uniprot:Q13472 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• microcephaly, growth restriction, and increased sister chromatid exchange 2 (Definitive), mode of inheritance: AR
• progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 5 (Strong), mode of inheritance: AR
• microcephaly, growth restriction, and increased sister chromatid exchange 2 (Strong), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Microcephaly, growth restriction, and increased sister chromatid exchange 2; Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 5	AR	Allergy/Immunology/Infectious; Cardiovascular	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	Allergy/Immunology/Infectious; Audiologic/Otolaryngologic; Cardiovascular; Craniofacial; Dermatologic; Musculoskeletal; Neurologic	29290614; 30057030

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the TOP3A gene.

• not provided (9 variants)
• Microcephaly, growth restriction, and increased sister chromatid exchange 2 (1 variants)
• Inborn genetic diseases (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the TOP3A gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous				102	6	108
missense			126	9	5	140
nonsense	3		1			4
start loss			1			1
frameshift	6	2	3			11
inframe indel			2			2
splice donor/acceptor (+/-2bp)		6				6
splice region			1	11	4	16
non coding			2	43	9	54
Total	9	8	135	154	20

Highest pathogenic variant AF is 0.0000592

Variants in TOP3A

This is a list of pathogenic ClinVar variants found in the TOP3A region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
17-18274804-ATCTGT-A			Uncertain significance (Dec 07, 2021)
17-18274818-CA-C			Uncertain significance (Aug 09, 2022)
17-18274827-C-CG			Uncertain significance (Aug 19, 2022)
17-18274834-G-A			Uncertain significance (May 16, 2022)
17-18274846-G-A			Uncertain significance (Jul 06, 2022)
17-18274862-C-T			Likely benign (Nov 14, 2022)
17-18274863-C-T			Uncertain significance (Dec 30, 2023)
17-18274905-C-T			Uncertain significance (Aug 09, 2022)
17-18274921-T-C			Uncertain significance (Apr 18, 2023)
17-18274928-C-T			Likely benign (Jul 10, 2023)
17-18274929-G-A		Inborn genetic diseases	Conflicting classifications of pathogenicity (Feb 10, 2023)
17-18274955-T-C			Likely benign (Oct 13, 2023)
17-18274976-A-T			Likely benign (Nov 17, 2022)
17-18274985-C-T			Likely benign (Jan 10, 2023)
17-18274998-G-A			Likely benign (Nov 04, 2023)
17-18275000-A-G			Likely benign (Jan 26, 2023)
17-18277661-C-T			Likely benign (Aug 28, 2022)
17-18277681-C-T		Inborn genetic diseases	Uncertain significance (Aug 21, 2023)
17-18277682-G-A			Benign/Likely benign (Jan 26, 2024)
17-18277682-G-T			Benign (Jan 04, 2024)
17-18277693-C-T			Uncertain significance (Feb 24, 2022)
17-18277694-G-A			Likely benign (Nov 27, 2023)
17-18277723-C-A		Microcephaly, growth restriction, and increased sister chromatid exchange 2	Uncertain significance (Feb 02, 2022)
17-18277727-C-T			Likely benign (May 18, 2022)
17-18277728-G-A		Inborn genetic diseases	Uncertain significance (Jul 08, 2022)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
TOP3A	protein_coding	protein_coding	ENST00000321105	19	43580

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
5.10e-11	1.00	125580	1	167	125748	0.000668

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.31	493	582	0.847	0.0000327	6548
Missense in 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

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000565	0.000563
Ashkenazi Jewish	0.0000992	0.0000992
East Asian	0.000277	0.000272
Finnish	0.000323	0.000323
European (Non-Finnish)	0.000581	0.000580
Middle Eastern	0.000277	0.000272
South Asian	0.00235	0.00232
Other	0.000326	0.000326

dbNSFP

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}.
• Pathway: 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;Gene expression (Transcription);DNA Double-Strand Break Repair;Generic Transcription Pathway;Homology Directed Repair;RNA Polymerase II Transcription;G2/M DNA damage checkpoint;G2/M Checkpoints;Cell Cycle Checkpoints;Fanconi anemia pathway;Regulation of TP53 Activity through Phosphorylation;Regulation of TP53 Activity;Transcriptional Regulation by TP53;Cell Cycle;Processing of DNA double-strand break ends;ATM pathway;Presynaptic phase of homologous DNA pairing and strand exchange;Homologous DNA Pairing and Strand Exchange;Resolution of D-loop Structures through Holliday Junction Intermediates;Resolution of D-loop Structures through Synthesis-Dependent Strand Annealing (SDSA);Resolution of D-Loop Structures;HDR through Homologous Recombination (HRR) (Consensus)

Recessive Scores

• pRec: 0.0939

Intolerance Scores

• loftool: 0.856
• rvis_EVS: 0.3
• rvis_percentile_EVS: 71.7

Haploinsufficiency Scores

• pHI: 0.562
• hipred: Y
• hipred_score: 0.706
• ghis: 0.492

Essentials

• essential_gene_CRISPR: E
• essential_gene_CRISPR2: E
• essential_gene_gene_trap: E
• gene_indispensability_pred: E
• gene_indispensability_score: 0.731

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Top3a
• Phenotype: cellular phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); embryo phenotype

Zebrafish Information Network

• Gene name: top3a
• Affected structure: T cell
• Phenotype tag: abnormal
• Phenotype quality: decreased amount

Gene ontology

• Biological process: DNA replication;DNA topological change;mitochondrial DNA metabolic process;chromosome separation;meiotic cell cycle
• Cellular component: nucleus;nucleoplasm;chromosome;mitochondrion;PML body
• Molecular function: DNA binding;single-stranded DNA binding;DNA topoisomerase activity;DNA topoisomerase type I activity;protein binding;zinc ion binding