14-89956564-C-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_018319.4(TDP1):c.-230-14C>A variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.251 in 152,240 control chromosomes in the GnomAD database, including 8,005 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.25 (8002 hom., cov: 33)
  • Exomes 𝑓: 0.13 (3 hom.)
• Consequence: TDP1 NM_018319.4 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.59

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 14-89956564-C-A is Benign according to our data. Variant chr14-89956564-C-A is described in ClinVar as [Benign]. Clinvar id is 314815.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr14-89956564-C-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.558 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TDP1	NM_018319.4	c.-230-14C>A		splice_polypyrimidine_tract_variant, intron_variant		ENST00000335725.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TDP1	ENST00000335725.9	c.-230-14C>A		splice_polypyrimidine_tract_variant, intron_variant		1	NM_018319.4	P1

Frequencies

GnomAD3 genomes AF: 0.251 AC: 38168 AN: 151964 Hom.: 7976 Cov.: 33

Gnomad AFR AF: 0.564

Gnomad AMI AF: 0.0285

Gnomad AMR AF: 0.284

Gnomad ASJ AF: 0.153

Gnomad EAS AF: 0.224

Gnomad SAS AF: 0.294

Gnomad FIN AF: 0.101

Gnomad MID AF: 0.146

Gnomad NFE AF: 0.0856

Gnomad OTH AF: 0.212

GnomAD4 exome AF: 0.131 AC: 21 AN: 160 Hom.: 3 Cov.: 0 AF XY: 0.115 AC XY: 14 AN XY: 122

Gnomad4 AFR exome AF: 0.500

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.250

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.125

Gnomad4 NFE exome AF: 0.117

Gnomad4 OTH exome AF: 0.250

GnomAD4 genome AF: 0.252 AC: 38259 AN: 152080 Hom.: 8002 Cov.: 33 AF XY: 0.254 AC XY: 18904 AN XY: 74366

Gnomad4 AFR AF: 0.564

Gnomad4 AMR AF: 0.285

Gnomad4 ASJ AF: 0.153

Gnomad4 EAS AF: 0.224

Gnomad4 SAS AF: 0.294

Gnomad4 FIN AF: 0.101

Gnomad4 NFE AF: 0.0856

Gnomad4 OTH AF: 0.218

Alfa AF: 0.180 Hom.: 579

Bravo AF: 0.278

Asia WGS AF: 0.306 AC: 1065 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
Cadd	Benign	1.3
Dann	Benign	0.60

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs28365055; hg19: chr14-90422908;