chr14-89993420-A-G
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong
The NM_018319.4(TDP1):āc.1478A>Gā(p.His493Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000806 in 1,613,830 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (ā ā ).
Frequency
Consequence
NM_018319.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
TDP1 | NM_018319.4 | c.1478A>G | p.His493Arg | missense_variant | Exon 14 of 17 | ENST00000335725.9 | NP_060789.2 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152232Hom.: 0 Cov.: 33
GnomAD4 exome AF: 0.00000684 AC: 10AN: 1461598Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4AN XY: 727112
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152232Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74376
ClinVar
Submissions by phenotype
Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 1 Pathogenic:5
This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -
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The highest allele frequency in gnomAD v4.0 is 0.0001335 (10/74916 alleles) in African/African American population). PP3_Strong: REVEL score is 0.95. PS3_Supporting: functional studies provide supportive evidence that the variant has a damaging effect on the gene or gene product (PMID:15920477,16141202). PS4 Met: this variant has been observed in >10 probands with consistent phenotype for disorder. Sequencing funded by the International Centre for Genomic Medicine in Neuromuscular Diseases (ICGNMD): https://www.ucl.ac.uk/genomic-medicine-neuromuscular-diseases/. -
This TDP1 variant (rs119467003) is absent from a large population dataset and has been reported in ClinVar. The histidine residue at this position is strongly conserved across the vertebrate species assessed. This amino acid substitution (p.His493Arg) changes a key active site residue that serves as a proton donor/acceptor. Functional studies demonstrate that this variant creates a TDP1-DNA covalent intermediate that results in reduced protein activity and altered protein function. This same variant has been detected in a homozygous state in three independent families with SCAN1. We consider c.1478A>G (p.His493Arg) to be pathogenic for autosomal recessive spinocerebellar ataxia with axonal neuropathy-1 (SCAN1). -
not provided Pathogenic:1
Published functional studies demonstrate that this variant creates a TDP1-DNA complex that results in reduced protein activity and altered protein function (Interthal et al., 2005a, Interthal et al. 2005b, Hirano et al. 2007); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 21463258, 21246735, 21167187, 22536944, 19883083, 22788692, 25024006, 25111769, 31723605, 24856239, 26601161, 17948061, 19139070, 22214184, 22522093, 23626666, 25841101, 29898404, 16141202, 19211312, 19476377, 21677033, 22155078, 24637157, 16935573, 19139134, 20687496, 20097655, 33425909, 15744309, 24236237, 31429931, 12244316, 31182267, 15920477) -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at