TDP1

protein-coding

tyrosyl-DNA phosphodiesterase 1

Gene summary

The protein encoded by this gene is involved in repairing stalled topoisomerase I-DNA complexes by catalyzing the hydrolysis of the phosphodiester bond between the tyrosine residue of topoisomerase I and the 3-prime phosphate of DNA. This protein may also remove glycolate from single-stranded DNA containing 3-prime phosphoglycolate, suggesting a role in repair of free-radical mediated DNA double-strand breaks. This gene is a member of the phospholipase D family and contains two PLD phosphodiesterase domains. Mutations in this gene are associated with the disease spinocerebellar ataxia with axonal neuropathy (SCAN1). [provided by RefSeq, Aug 2016]

MANE transcript

NM_018319.4

Inheritance

ClinVar variants

P:9U:144B:28

Top phenotype

Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 1

gnomAD constraint

pLI —, LoF o/e 0.82

Max pathogenic AF

—

Genomic locus

chr14:89,954,939-90,044,764

External References & Databases

Ensembl (ENSG00000042088)

Transcript & Mutation Effects

hg38 • Region Span ~89.8 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

male infertility with azoospermia or oligozoospermia due to single gene mutationNO_KNOWN

Inheritance Pattern: AR

Disease ID:MONDO:0018393

Submitter: King Faisal Specialist Hospital and Research Center

Convincing evidence disputing a role for this gene is this disease has arisen since the initial report identifying a gene for Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy (PMID:12244316). Alhathal et al., 2020 (PMID: 32719396) reported two unique variants (including nonesense and missense) in male infertility cohort and none of them having brain involvement (PMID: 32719396).

spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 1LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0011801

Submitter: Ambry Genetics

spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 1MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0011801

Submitter: PanelApp Australia

spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 1STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011801

Submitter: Labcorp Genetics (formerly Invitae)

spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 1SUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011801

Submitter: Orphanet

Clinical Genomic Database (CGD)

Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 1AR

Manifestation: Neurologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 12244316

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TDP1 variants in ClinVar

5 Conditions Cataloged

not providedTotal: 107

not specifiedTotal: 105

Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 1Total: 47

TDP1-related disorderTotal: 11

Myoepithelial tumorTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_018319.4. 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			6 clinvar	16 clinvar	3 clinvar	25
missense	1 clinvar		126 clinvar	9 clinvar		136
nonsense		3 clinvar	2 clinvar			5
start loss		1 clinvar				1
frameshift		3 clinvar	4 clinvar			7
splice donor/acceptor (+/-2bp)		1 clinvar	6 clinvar			7
Total	1	8	144	25	3	181

Highest pathogenic variant AF is 0.000034078053

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 69 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_018319.4	RefSeq	NP_060789.2	15	MANE Select
ENST00000335725.9	Ensembl	ENSP00000337353.4	15	MANE Select
NM_001008744.2	RefSeq	NP_001008744.1	15	Standard
NM_001330205.2	RefSeq	NP_001317134.1	14	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

DNA Repair
Nonhomologous End-Joining (NHEJ)
DNA Double-Strand Break Repair

Biological Process

single strand break repair
DNA repair
double-strand break repair
nucleic acid phosphodiester bond hydrolysis

Molecular Function

double-stranded DNA binding
single-stranded DNA binding
exonuclease activity
protein binding
3'-tyrosyl-DNA phosphodiesterase activity

Cellular Component

nucleus
cytoplasm
plasma membrane
intracellular membrane-bounded organelle

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000335725
Coding exons: 15
Length: 89824
Individuals with no LoFs: 125629
Homozygous LoFs: 0
Heterozygous LoFs: 119
Defined: 125748
p: 0.000473

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.599	303	334	0.908	0.0000177	4008
Missense (PolyPhen)		105	126.53	0.82985		1517
Synonymous	0.482	119	126	0.945	0.00000774	1119
Loss of Function	1.03	30	36.8	0.816	0.00000186	427

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00025	0.00025	rare
Latino/Admixed American	0.00067	0.00067	rare
Ashkenazi Jewish	0.00050	0.00050	rare
East Asian	0.00033	0.00033	rare
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.00055	0.00055	rare
South Asian	0.00046	0.00046	rare
Other	0.00065	0.00065	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: DNA repair enzyme that can remove a variety of covalent adducts from DNA through hydrolysis of a 3'-phosphodiester bond, giving rise to DNA with a free 3' phosphate. Catalyzes the hydrolysis of dead-end complexes between DNA and the topoisomerase I active site tyrosine residue. Hydrolyzes 3'-phosphoglycolates on protruding 3' ends on DNA double-strand breaks due to DNA damage by radiation and free radicals. Acts on blunt-ended double-strand DNA breaks and on single-stranded DNA. Has low 3'exonuclease activity and can remove a single nucleoside from the 3'end of DNA and RNA molecules with 3'hydroxyl groups. Has no exonuclease activity towards DNA or RNA with a 3'phosphate. {ECO:0000269|PubMed:12023295, ECO:0000269|PubMed:15111055, ECO:0000269|PubMed:15811850, ECO:0000269|PubMed:16141202, ECO:0000269|PubMed:22822062}.;
Disease: DISEASE: Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy (SCAN1) [MIM:607250]: Spinocerebellar ataxia is a clinically and genetically heterogeneous group of cerebellar disorders. Patients show progressive incoordination of gait and often poor coordination of hands, speech and eye movements, due to degeneration of the cerebellum with variable involvement of the brainstem and spinal cord. SCAN1 is an autosomal recessive cerebellar ataxia (ARCA) associated with peripheral axonal motor and sensory neuropathy, distal muscular atrophy, pes cavus and steppage gait as seen in Charcot-Marie-Tooth neuropathy. All affected individuals have normal intelligence. {ECO:0000269|PubMed:12244316, ECO:0000269|PubMed:15647511, ECO:0000269|PubMed:15920477, ECO:0000269|PubMed:16141202, ECO:0000269|PubMed:17948061}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.131

Intolerance Scores

LoFtool: 0.994
RVIS EVS: -0.51
RVIS percentile EVS: 21.77

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.773

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium