TOPBP1

Chr 3

DNA topoisomerase II binding protein 1

Also known as: Dpb11, TOP2BP1

NCBI Gene: 11073 ENSG00000163781 UniProt: Q92547 OMIM: 607760

This gene encodes a binding protein which interacts with the C-terminal region of topoisomerase II beta. This interaction suggests a supportive role for this protein in the catalytic reactions of topoisomerase II beta through transient breakages of DNA strands. [provided by RefSeq, Jul 2008]

OMIM Research

OMIM ResearchGenerating clinical summary…

LOFmechanismLOEUF 0.09

Clinical Summary— TOPBP1

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Gene-Disease Validity (ClinGen)

pulmonary arterial hypertension · ADNo Known Disease Relationship

No known disease relationship

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

184 VUS of 258 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.09LOEUF

pLI 1.000

Z-score 7.70

OE 0.03 (0.01–0.09)

Highly constrained

Among the most LoF-intolerant genes (~top 3%)

Missense Constraint?

1.97Z-score

OE missense 0.80 (0.75–0.85)

610 obs / 763.2 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.03 (0.01–0.09)

0≤0.351.4

Missense OE?0.80 (0.75–0.85)

0≤0.61.4

Synonymous OE?1.04

0≤1.21.6

LoF obs/exp: 2 / 72.9Missense obs/exp: 610 / 763.2Syn Z: -0.45

This gene — mechanism propensity

0.3395th %ile

GOF

0.2597th %ile

LOF

0.68top 10%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · LOEUF 0.09

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

258 submitted variants in ClinVar

ClinVar

Classification Summary

VUS184

Likely Benign20

Benign10

Conflicting1

184

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	0	0
Likely Pathogenic	0	0	0	0	0
VUS	0	184	0	0	184
Likely Benign	0	11	2	7	20
Benign	0	6	1	3	10
Conflicting	—				1
Total	0	201	3	10	215

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

View in ClinVar →

15 pathogenic / likely-pathogenic (of 16) ClinVar copy-number / structural variants overlap TOPBP1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →