rs7149962

Variant names:

• chr14-89995982-A-C
• rs7149962
• NM_018319.4:c.1541+2499A>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_018319.4(TDP1):​c.1541+2499A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.123 in 152,226 control chromosomes in the GnomAD database, including 2,723 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 0.12 (2723 hom., cov: 32)
• Consequence: TDP1 NM_018319.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.318
• Publications: 3 publications found

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]

TDP1 Gene-Disease associations (from GenCC):

• spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 1

  Inheritance: AR Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• male infertility with azoospermia or oligozoospermia due to single gene mutation

  Inheritance: AR Classification: NO_KNOWN Submitted by: King Faisal Specialist Hospital and Research Center

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.347 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TDP1	NM_018319.4	c.1541+2499A>C		intron_variant	Intron 14 of 16	ENST00000335725.9	NP_060789.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TDP1	ENST00000335725.9	c.1541+2499A>C		intron_variant	Intron 14 of 16	1	NM_018319.4	ENSP00000337353.4

Frequencies

GnomAD3 genomes AF: 0.122 AC: 18627 AN: 152108 Hom.: 2715 Cov.: 32

Gnomad AFR AF: 0.351

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0848

Gnomad ASJ AF: 0.0916

Gnomad EAS AF: 0.0235

Gnomad SAS AF: 0.0811

Gnomad FIN AF: 0.0263

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.0214

Gnomad OTH AF: 0.101

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.123 AC: 18679 AN: 152226 Hom.: 2723 Cov.: 32 AF XY: 0.120 AC XY: 8958 AN XY: 74448

African (AFR) AF: 0.351 AC: 14574 AN: 41468

American (AMR) AF: 0.0847 AC: 1296 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0916 AC: 318 AN: 3472

East Asian (EAS) AF: 0.0236 AC: 122 AN: 5176

South Asian (SAS) AF: 0.0810 AC: 391 AN: 4830

European-Finnish (FIN) AF: 0.0263 AC: 280 AN: 10628

Middle Eastern (MID) AF: 0.0748 AC: 22 AN: 294

European-Non Finnish (NFE) AF: 0.0214 AC: 1456 AN: 68030

Other (OTH) AF: 0.104 AC: 219 AN: 2114

Alfa AF: 0.0895 Hom.: 229

Bravo AF: 0.137

Asia WGS AF: 0.0740 AC: 261 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	4.5
DANN	Benign	0.79
PhyloP100		-0.32
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs7149962; hg19: chr14-90462326;