TOP3B

Chr 22

DNA topoisomerase III beta

Also known as: TOP3B1

NCBI Gene: 8940ENSG00000100038UniProt: O95985

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 relaxing the supercoils and altering the topology of DNA. The enzyme interacts with DNA helicase SGS1 and plays a role in DNA recombination, cellular aging and maintenance of genome stability. Low expression of this gene may be related to higher survival rates in breast cancer patients. This gene has a pseudogene on chromosome 22. Alternate splicing results in multiple transcript variants. Additional alternatively spliced transcript variants of this gene have been described, but their full-length nature is not known. [provided by RefSeq, Aug 2013]

293
ClinVar variants
91
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— TOP3B
⚡
Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.34) despite low pLI — interpret in context.
📋
ClinVar Variants
91 Pathogenic / Likely Pathogenic· 144 VUS of 293 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Moderate LoF intolerance
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.54LOEUF
pLI 0.000
Z-score 3.88
OE 0.34 (0.23–0.54)
Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
2.23Z-score
OE missense 0.73 (0.67–0.79)
381 obs / 524.5 exp
Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.34 (0.23–0.54)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.73 (0.67–0.79)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.99
0≤1.21.6
LoF obs/exp: 14 / 40.7Missense obs/exp: 381 / 524.5Syn Z: 0.14

ClinVar Variant Classifications

293 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic83
Likely Pathogenic8
VUS144
Likely Benign23
Benign18
83
Pathogenic
8
Likely Pathogenic
144
VUS
23
Likely Benign
18
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
83
0
83
Likely Pathogenic
0
0
8
0
8
VUS
1
120
23
0
144
Likely Benign
0
5
5
13
23
Benign
0
4
10
4
18
Total112912917276

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

TOP3B · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Genetic Alterations in a Large Population of Italian Patients Affected by Neurodevelopmental Disorders.
Ranieri A et al.·Genes (Basel)
2024Cohort
Further evidence of GABRA4 and TOP3B as autism susceptibility genes.
Riley JD et al.·Eur J Med Genet
2020Case report
Genomic landscape and molecular evolutionary trajectories of renal epithelioid angiomyolipoma and benign angiomyolipoma.
Anwaier A et al.·Neoplasia
2025
Deletion of TOP3B Is Associated with Cognitive Impairment and Facial Dysmorphism.
Kaufman CS et al.·Cytogenet Genome Res
2016Case report
Genetic characterisation of 22q11.2 variations and prevalence in patients with congenital heart disease.
Hou HT et al.·Arch Dis Child
2020Cohort
Clinical presentation and genetic profiles of Chinese patients with velocardiofacial syndrome in a large referral centre.
Wu D et al.·J Genet
2019Cohort
Mining expression and prognosis of topoisomerase isoforms in non-small-cell lung cancer by using Oncomine and Kaplan-Meier plotter.
Hou GX et al.·PLoS One
2017
Experience of the first adult-focussed undiagnosed disease program in Australia (AHA-UDP): solving rare and puzzling genetic disorders is ageless.
Wallis M et al.·Orphanet J Rare Dis
2024
Mexican Patients With Suspected 22q11.2 Deletion Syndrome: Clinical Characterization and Molecular Findings by Fluorescence In Situ Hybridization and Multiplex Ligation-Dependent Probe Amplification.
Aguayo-Orozco TA et al.·Mol Genet Genomic Med
2025Cohort
Substituted Triazole-3,5-Diamine Compounds as Novel Human Topoisomerase III Beta Inhibitors.
Mamun Y et al.·Int J Mol Sci
2025
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools