TDP1

tyrosyl-DNA phosphodiesterase 1

Basic information

Region (hg38): 14:89954939-90044764

Links

ENSG00000042088 ∙ NCBI:55775 ∙ OMIM:607198 ∙ HGNC:18884 ∙ Uniprot:Q9NUW8 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• male infertility with azoospermia or oligozoospermia due to single gene mutation (Disputed Evidence), mode of inheritance: AR
• spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 1 (Supportive), mode of inheritance: AR
• spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 1 (Strong), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 1	AR	General	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	Neurologic	12244316

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the TDP1 gene.

• not provided (1 variants)
• Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 1 (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the TDP1 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			3	8	7	18
missense	1		79	5	2	87
nonsense		1	1			2
start loss		1				1
frameshift		1	1			2
inframe indel						0
splice donor/acceptor (+/-2bp)						0
splice region		1	4	2		7
non coding			36	14	50	100
Total	1	3	120	27	59

Highest pathogenic variant AF is 0.0000197

Variants in TDP1

This is a list of pathogenic ClinVar variants found in the TDP1 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
14-89955909-G-T		Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 1	Uncertain significance (Jan 12, 2018)
14-89955920-G-GGCC		Autosomal recessive cerebellar ataxia	Benign (Jun 14, 2016)
14-89955923-C-T		Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 1	Uncertain significance (Jan 13, 2018)
14-89955926-C-G		Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 1	Uncertain significance (Jan 13, 2018)
14-89955937-G-A		Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 1	Uncertain significance (Jan 12, 2018)
14-89955958-C-T		Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 1	Uncertain significance (Jan 13, 2018)
14-89955959-T-G		Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 1	Uncertain significance (Jan 12, 2018)
14-89955969-A-C		Autosomal recessive cerebellar ataxia	Uncertain significance (Jun 14, 2016)
14-89956564-C-A		Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 1	Benign (Jan 13, 2018)
14-89956574-G-T		Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 1	Benign (Jan 12, 2018)
14-89956584-A-G		Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 1	Benign (Jan 13, 2018)
14-89956631-C-T		Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 1	Benign (Jan 12, 2018)
14-89956732-T-C		Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 1	Uncertain significance (Jan 13, 2018)
14-89956753-C-G		Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 1	Uncertain significance (Jan 13, 2018)
14-89956770-G-A		Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 1	Uncertain significance (Jan 13, 2018)
14-89956787-C-T		Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 1	Benign (Jan 13, 2018)
14-89956815-T-C		Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 1	Uncertain significance (Jan 13, 2018)
14-89962826-T-C			Benign (Jun 05, 2021)
14-89963112-A-G			Uncertain significance (Oct 23, 2015)
14-89963116-T-G			Likely pathogenic (Mar 14, 2018)
14-89963129-C-T		Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 1	Uncertain significance (Oct 26, 2018)
14-89963130-G-A			Uncertain significance (Apr 01, 2021)
14-89963133-T-C		Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 1 • not specified	Uncertain significance (Nov 14, 2023)
14-89963134-A-G		not specified	Uncertain significance (Apr 23, 2024)
14-89963139-A-G		Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 1	Uncertain significance (Jan 13, 2018)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
TDP1	protein_coding	protein_coding	ENST00000335725	15	89824

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.27e-17	0.0737	125629	0	119	125748	0.000473

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.599	303	334	0.908	0.0000177	4008
Missense in 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

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000912	0.000912
Ashkenazi Jewish	0.000496	0.000496
East Asian	0.000327	0.000326
Finnish	0.0000462	0.0000462
European (Non-Finnish)	0.000546	0.000545
Middle Eastern	0.000327	0.000326
South Asian	0.000458	0.000457
Other	0.000653	0.000652

dbNSFP

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.
• Pathway: DNA Repair;Nonhomologous End-Joining (NHEJ);DNA Double-Strand Break Repair (Consensus)

Recessive Scores

• pRec: 0.131

Intolerance Scores

• loftool: 0.994
• rvis_EVS: -0.51
• rvis_percentile_EVS: 21.77

Haploinsufficiency Scores

• pHI: 0.223
• hipred: Y
• hipred_score: 0.515
• ghis: 0.657

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.773

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Tdp1
• Phenotype: homeostasis/metabolism phenotype; cellular phenotype; nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan)

Gene ontology

• Biological process: single strand break repair;DNA repair;double-strand break repair;nucleic acid phosphodiester bond hydrolysis
• Cellular component: nucleus;cytoplasm;plasma membrane;intracellular membrane-bounded organelle
• Molecular function: double-stranded DNA binding;single-stranded DNA binding;exonuclease activity;protein binding;3'-tyrosyl-DNA phosphodiesterase activity