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…

Clinical highlights

Gene–disease validity (ClinGen)

Refuted · pulmonary arterial hypertension · AD · ClinGen 2022

evidence has disproved this relationship

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Based on population constraint only.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.09

LOEUF· LoF intol.

LOF

Mechanism· predicted

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

Background carrier burden — how many people carry a rare variant somewhere in TOPBP1?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 33

1,666 rare PASS variants

Rare truncating (LoF)

1 in 3,400

87 rare PASS variants

Rare synonymous (reference)

1 in 95

640 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for TOPBP1. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 49	1 in 3,800
South Asian	~43k	1 in 28	1 in 2,000
Remaining (unassigned)	~30k	1 in 29	1 in 4,200
European (Finnish)	~27k	1 in 170	1 in 2,900
Admixed American	~22k	1 in 34	1 in 1,500
African / African American	~21k	1 in 31	1 in 2,900
East Asian	~20k	1 in 42	1 in 1,600
Ashkenazi Jewish	~13k	1 in 140	1 in 2,400
Middle Eastern	~2,884	1 in 28	none seen

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 24 of 27 coding exons well covered in gnomAD exomes; exons 6, 23, 28 marginal. Genomes: all 27.? see exons ↓