TOP1
protein-codingDNA topoisomerase I, the group of Topoisomerases
Gene summary
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 altering the topology of DNA. This gene is localized to chromosome 20 and has pseudogenes which reside on chromosomes 1 and 22. [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 ~95.7 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
No GenCC data available for this gene.
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to TOP1 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_003286.4. 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 | 1 | 4 | 5 | 10 | ||
| missense | 1 | 41 | 1 | 43 | ||
| nonsense | 2 | 2 | ||||
| start loss | 0 | |||||
| frameshift | 0 | |||||
| splice donor/acceptor (+/-2bp) | 6 | 6 | ||||
| Total | 1 | 0 | 50 | 4 | 6 | 61 |
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_003277.1 | 21 | MANE Select | |
| Ensembl | ENSP00000354522.2 | 21 | MANE Select | |
| Ensembl | ENSP00000504935.1 | 8 | Standard | |
| Ensembl | ENSP00000505788.1 | 9 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Irinotecan Pathway, Pharmacodynamics
- Irinotecan Action Pathway
- Irinotecan Metabolism Pathway
- Post-translational protein modification
- SUMOylation of DNA replication proteins
Biological Process
- DNA replication
- DNA topological change
- chromatin remodeling
- chromosome segregation
- circadian rhythm
Molecular Function
- RNA polymerase II proximal promoter sequence-specific DNA binding
- DNA binding
- chromatin binding
- double-stranded DNA binding
- single-stranded DNA binding
Cellular Component
- nuclear chromosome
- P-body
- fibrillar center
- nucleus
- nucleoplasm
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000361337
- Coding exons
- 21
- Length
- 95670
- Individuals with no LoFs
- 0
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 0
- Defined
- 0
- p
- 0.00
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 4.47 | 156 | 411 | 0.379 | 0.0000222 | 5162 |
| Missense (PolyPhen) | 11 | 143.53 | 0.076639 | 1747 | ||
| Synonymous | 0.710 | 127 | 138 | 0.923 | 0.00000704 | 1252 |
| Loss of Function | 6.57 | 0 | 50.3 | 0.00 | 0.00000304 | 597 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0 | 0.0 | absent |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0 | 0.0 | absent |
| South Asian | 0 | 0.0 | absent |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Releases the supercoiling and torsional tension of DNA introduced during the DNA replication and transcription by transiently cleaving and rejoining one strand of the DNA duplex. Introduces a single-strand break via transesterification at a target site in duplex DNA. The scissile phosphodiester is attacked by the catalytic tyrosine of the enzyme, resulting in the formation of a DNA-(3'-phosphotyrosyl)-enzyme intermediate and the expulsion of a 5'-OH DNA strand. The free DNA strand then rotates around the intact phosphodiester bond on the opposing strand, thus removing DNA supercoils. Finally, in the religation step, the DNA 5'-OH attacks the covalent intermediate to expel the active-site tyrosine and restore the DNA phosphodiester backbone (By similarity). Regulates the alternative splicing of tissue factor (F3) pre-mRNA in endothelial cells. Involved in the circadian transcription of the core circadian clock component ARNTL/BMAL1 by altering the chromatin structure around the ROR response elements (ROREs) on the ARNTL/BMAL1 promoter. {ECO:0000250|UniProtKB:Q13472, ECO:0000269|PubMed:14594810, ECO:0000269|PubMed:16033260, ECO:0000269|PubMed:19168442, ECO:0000269|PubMed:22904072, ECO:0000269|PubMed:2833744}.;
- Disease
- DISEASE: Note=A chromosomal aberration involving TOP1 is found in a form of therapy-related myelodysplastic syndrome. Translocation t(11;20)(p15;q11) with NUP98. {ECO:0000269|PubMed:10556215}.;
Recessive Scores
- pRec
- 0.808
Intolerance Scores
- RVIS EVS
- -0.38
- RVIS percentile EVS
- 27.69
Essentials
- Essential (CRISPR)
- E
- Essential (CRISPR2)
- E
- Essential (gene trap)
- E
- Indispensability pred.
- E
- Indispensability score
- 0.956
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |