NM_018319.4:c.-21C>T

Variant names:

• chr14-89956787-C-T
• rs34348197
• NM_018319.4:c.-21C>T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_018319.4(TDP1):​c.-21C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0735 in 152,300 control chromosomes in the GnomAD database, including 724 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.074 (724 hom., cov: 33)
  • Exomes 𝑓: 0.051 (0 hom.)
• Consequence: TDP1 NM_018319.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.637

Genes affected

TDP1 (HGNC:18884): (tyrosyl-DNA phosphodiesterase 1) 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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 14-89956787-C-T is Benign according to our data. Variant chr14-89956787-C-T is described in ClinVar as [Benign]. Clinvar id is 314821.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-89956787-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.207 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TDP1	NM_018319.4	c.-21C>T		5_prime_UTR_variant	Exon 2 of 17	ENST00000335725.9	NP_060789.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TDP1	ENST00000335725	c.-21C>T		5_prime_UTR_variant	Exon 2 of 17	1	NM_018319.4	ENSP00000337353.4

Frequencies

GnomAD3 genomes AF: 0.0734 AC: 11168 AN: 152102 Hom.: 719 Cov.: 33

Gnomad AFR AF: 0.0170

Gnomad AMI AF: 0.0274

Gnomad AMR AF: 0.184

Gnomad ASJ AF: 0.0573

Gnomad EAS AF: 0.200

Gnomad SAS AF: 0.217

Gnomad FIN AF: 0.0757

Gnomad MID AF: 0.0538

Gnomad NFE AF: 0.0641

Gnomad OTH AF: 0.0798

GnomAD4 exome AF: 0.0513 AC: 4 AN: 78 Hom.: 0 Cov.: 0 AF XY: 0.0517 AC XY: 3 AN XY: 58

Gnomad4 AFR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.250

Gnomad4 EAS exome AF: 0.500

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0200

Gnomad4 OTH exome AF: 0.125

GnomAD4 genome AF: 0.0735 AC: 11194 AN: 152222 Hom.: 724 Cov.: 33 AF XY: 0.0810 AC XY: 6032 AN XY: 74428

Gnomad4 AFR AF: 0.0169

Gnomad4 AMR AF: 0.185

Gnomad4 ASJ AF: 0.0573

Gnomad4 EAS AF: 0.201

Gnomad4 SAS AF: 0.218

Gnomad4 FIN AF: 0.0757

Gnomad4 NFE AF: 0.0641

Gnomad4 OTH AF: 0.0833

Alfa AF: 0.0689 Hom.: 75

Bravo AF: 0.0788

Asia WGS AF: 0.211 AC: 732 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 1 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	6.1
DANN	Benign	0.79

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs34348197; hg19: chr14-90423131;