TOP3A

Chr 17AR

DNA topoisomerase III alpha

Also known as: MGRISCE2, PEOB5, TOP3, ZGRF7

NCBI Gene: 7156 ENSG00000177302 UniProt: Q13472 OMIM: 601243

The protein functions as a DNA topoisomerase that relieves supercoiling tension during DNA replication and transcription by transiently cleaving and rejoining single DNA strands, and is essential for mitochondrial DNA decatenation and segregation. Biallelic mutations cause autosomal recessive disorders including microcephaly with growth restriction and increased sister chromatid exchange, as well as progressive external ophthalmoplegia with mitochondrial DNA deletions. This gene is highly constrained against loss-of-function mutations (pLI near 1.0), indicating intolerance to protein truncation.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 0.682 OMIM phenotypes

Clinical Summary— TOP3A

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

39 unique Pathogenic / Likely Pathogenic· 211 VUS of 519 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — TOP3A

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.68LOEUF

pLI 0.000

Z-score 3.42

OE 0.49 (0.36–0.68)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.31Z-score

OE missense 0.85 (0.79–0.91)

493 obs / 582.0 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.49 (0.36–0.68)

0≤0.351.4

Missense OE?0.85 (0.79–0.91)

0≤0.61.4

Synonymous OE?1.09

0≤1.21.6

LoF obs/exp: 26 / 52.8Missense obs/exp: 493 / 582.0Syn Z: -1.08

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveTOP3A-related Bloom syndrome like disorderLOFAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.7035th %ile

GOF

0.5465th %ile

LOF

0.2969th %ile

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

519 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic24

Likely Pathogenic15

VUS211

Likely Benign210

Benign25

Conflicting14

Pathogenic

Likely Pathogenic

211

VUS

210

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	21	2	1	0	24
Likely Pathogenic	13	1	1	0	15
VUS	5	198	8	0	211
Likely Benign	0	6	74	130	210
Benign	0	5	13	7	25
Conflicting	—				14
Total	39	212	97	137	499

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

View in ClinVar →

116 pathogenic / likely-pathogenic (of 122) ClinVar copy-number / structural variants overlap TOP3A — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →