rs4143999

Positions:

• chr14-89955149-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The XM_011536942.4(TDP1):​c.-536G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.154 in 157,512 control chromosomes in the GnomAD database, including 2,761 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.16 (2709 hom., cov: 33)
  • Exomes 𝑓: 0.11 (52 hom.)
• Consequence: TDP1 XM_011536942.4 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.934

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.299 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TDP1	XM_011536942.4	c.-536G>A		5_prime_UTR_variant	1/16		XP_011535244.1
TDP1	XM_047431570.1	c.-759G>A		5_prime_UTR_variant	1/17		XP_047287526.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TDP1	ENST00000554976.5	n.-759G>A		non_coding_transcript_exon_variant	1/18	2		ENSP00000452042.1
TDP1	ENST00000554976.5	n.-759G>A		5_prime_UTR_variant	1/18	2		ENSP00000452042.1

Frequencies

GnomAD3 genomes AF: 0.155 AC: 23619 AN: 152092 Hom.: 2700 Cov.: 33

Gnomad AFR AF: 0.304

Gnomad AMI AF: 0.0274

Gnomad AMR AF: 0.212

Gnomad ASJ AF: 0.0706

Gnomad EAS AF: 0.201

Gnomad SAS AF: 0.218

Gnomad FIN AF: 0.0759

Gnomad MID AF: 0.0823

Gnomad NFE AF: 0.0637

Gnomad OTH AF: 0.135

GnomAD4 exome AF: 0.109 AC: 577 AN: 5302 Hom.: 52 Cov.: 0 AF XY: 0.118 AC XY: 356 AN XY: 3026

Gnomad4 AFR exome AF: 0.161

Gnomad4 AMR exome AF: 0.230

Gnomad4 ASJ exome AF: 0.100

Gnomad4 EAS exome AF: 0.173

Gnomad4 SAS exome AF: 0.201

Gnomad4 FIN exome AF: 0.0747

Gnomad4 NFE exome AF: 0.0639

Gnomad4 OTH exome AF: 0.0977

GnomAD4 genome AF: 0.156 AC: 23680 AN: 152210 Hom.: 2709 Cov.: 33 AF XY: 0.160 AC XY: 11910 AN XY: 74424

Gnomad4 AFR AF: 0.304

Gnomad4 AMR AF: 0.213

Gnomad4 ASJ AF: 0.0706

Gnomad4 EAS AF: 0.201

Gnomad4 SAS AF: 0.218

Gnomad4 FIN AF: 0.0759

Gnomad4 NFE AF: 0.0637

Gnomad4 OTH AF: 0.138

Alfa AF: 0.0921 Hom.: 1164

Bravo AF: 0.172

Asia WGS AF: 0.231 AC: 802 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
CADD	Benign	7.1
DANN	Benign	0.88

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs4143999; hg19: chr14-90421493;