14-89956584-A-G

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.-224A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0523 in 152,312 control chromosomes in the GnomAD database, including 343 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.052 (343 hom., cov: 33)
  • Exomes 𝑓: 0.033 (0 hom.)
• Consequence: TDP1 NM_018319.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.471

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=-0.79).
• BP6: Variant 14-89956584-A-G is Benign according to our data. Variant chr14-89956584-A-G is described in ClinVar as [Benign]. Clinvar id is 314817.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr14-89956584-A-G is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.11 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TDP1	NM_018319.4	c.-224A>G		5_prime_UTR_variant	2/17	ENST00000335725.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TDP1	ENST00000335725.9	c.-224A>G		5_prime_UTR_variant	2/17	1	NM_018319.4	P1

Frequencies

GnomAD3 genomes AF: 0.0523 AC: 7957 AN: 152074 Hom.: 343 Cov.: 33

Gnomad AFR AF: 0.113

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0532

Gnomad ASJ AF: 0.0817

Gnomad EAS AF: 0.0233

Gnomad SAS AF: 0.0672

Gnomad FIN AF: 0.0256

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.0201

Gnomad OTH AF: 0.0436

GnomAD4 exome AF: 0.0333 AC: 4 AN: 120 Hom.: 0 Cov.: 0 AF XY: 0.0333 AC XY: 3 AN XY: 90

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0313

Gnomad4 OTH exome AF: 0.167

GnomAD4 genome AF: 0.0524 AC: 7968 AN: 152192 Hom.: 343 Cov.: 33 AF XY: 0.0528 AC XY: 3928 AN XY: 74420

Gnomad4 AFR AF: 0.113

Gnomad4 AMR AF: 0.0531

Gnomad4 ASJ AF: 0.0817

Gnomad4 EAS AF: 0.0233

Gnomad4 SAS AF: 0.0672

Gnomad4 FIN AF: 0.0256

Gnomad4 NFE AF: 0.0201

Gnomad4 OTH AF: 0.0469

Alfa AF: 0.0337 Hom.: 42

Bravo AF: 0.0558

Asia WGS AF: 0.0550 AC: 194 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	-0.79
Cadd	Benign	8.1
Dann	Benign	0.63

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: rs35439694; hg19: chr14-90422928;