TOPBP1
protein-codingDNA topoisomerase II binding protein 1, the group of BRCA1 B complex
Gene summary
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]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~64.2 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0015924
Submitter: ClinGen
*TOPBP1* (topoisomerase IIβ-binding protein 1 ) encodes protein which is involved in DNA replication, especially in DNA damage repair (PMID:20012580). *TOPBP1* was first suggested in connection with autosomal dominant PAH in 2014 after 3 variants (rs55633281, rs17301766 and rs10935070) were identified in a cohort of 12 IPAH patients (Perez et al., PMID: 24702692). These variants are common (allele frequency >5% in multiple populations), and therefore were not scored as a part of this curation. There have been other case-control studies performed, all of which do not show a significant difference in the frequency of the previously mentioned *TOPBP1* variants (PMID:30084161) or other rare variants (PMID:29650961) between PAH patients and controls. Functionally, expression of *TOPBP1* was shown to be reduced in PAH patient cells. Furthermore, siRNA knockdown of *TOPB1* in control cells resulted in altered tube formation in PMVECs (pulmonary microvascular endothelial cells) in vitro. Subsequently, overexpression of *TOPBP1* rescued the tube malformations in PAH patient PMVECs (PMID:24702692). In summary, due to. the. lack. of genetic. evidence, *TOPBP1* has no known disease relationship with autosomal dominant PAH. This classification was approved by the ClinGen Pulmonary Hypertension GCEP on the meeting date 8/30/22 (SOP Version 9).
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to TOPBP1 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_007027.4. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 5 | 7 | 12 | |||
| missense | 191 | 15 | 3 | 209 | ||
| nonsense | 0 | |||||
| start loss | 0 | |||||
| frameshift | 0 | |||||
| splice donor/acceptor (+/-2bp) | 5 | 5 | ||||
| Total | 0 | 0 | 201 | 22 | 3 | 226 |
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_008958.2 | 27 | MANE Select | |
| Ensembl | ENSP00000260810.5 | 27 | MANE Select | |
| RefSeq | NP_001350818.1 | 27 | Standard | |
| Ensembl | ENSP00000458790.1 | 2 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| topbp1 | Danio rerio | Structure: hematopoietic stem cell homeostasis Quality: decreased process quality abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Homologous recombination - Homo sapiens (human)
- ATR Signaling
- HDR through Single Strand Annealing (SSA)
- HDR through Homologous Recombination (HR) or Single Strand Annealing (SSA)
- DNA Repair
Biological Process
- DNA metabolic process
- DNA repair
- cellular response to DNA damage stimulus
- response to ionizing radiation
- mitotic DNA replication checkpoint
Molecular Function
- DNA binding
- protein binding
- protein C-terminus binding
- identical protein binding
Cellular Component
- condensed nuclear chromosome
- spindle pole
- male germ cell nucleus
- nucleus
- nucleoplasm
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000260810
- Coding exons
- 27
- Length
- 63719
- Individuals with no LoFs
- 124643
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 9
- Defined
- 124652
- p
- 0.0000361
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 1.97 | 610 | 763 | 0.799 | 0.0000389 | 9976 |
| Missense (PolyPhen) | 122 | 197.54 | 0.61758 | 2508 | ||
| Synonymous | -0.455 | 276 | 267 | 1.04 | 0.0000140 | 2843 |
| Loss of Function | 7.70 | 2 | 72.9 | 0.0274 | 0.00000384 | 953 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.000065 | 0.000065 | rare |
| Latino/Admixed American | 0.000033 | 0.000029 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.000056 | 0.000056 | rare |
| Finnish | 0.00014 | 0.00014 | rare |
| European (Non-Finnish) | 0.000028 | 0.000027 | rare |
| South Asian | 0 | 0.0 | absent |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Required for DNA replication. Plays a role in the rescue of stalled replication forks and checkpoint control. Binds double- stranded DNA breaks and nicks as well as single-stranded DNA. Recruits the SWI/SNF chromatin remodeling complex to E2F1- responsive promoters. Down-regulates E2F1 activity and inhibits E2F1-dependent apoptosis during G1/S transition and after DNA damage. Induces a large increase in the kinase activity of ATR (PubMed:16530042). {ECO:0000269|PubMed:10498869, ECO:0000269|PubMed:11395493, ECO:0000269|PubMed:11714696, ECO:0000269|PubMed:12697828, ECO:0000269|PubMed:15075294, ECO:0000269|PubMed:16530042}.;
Recessive Scores
- pRec
- 0.182
Intolerance Scores
- RVIS EVS
- -0.37
- RVIS percentile EVS
- 28.29
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- E
- Essential (gene trap)
- E
- Indispensability pred.
- E
- Indispensability score
- 0.673
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |