rs7143875

Variant names:

• chr14-89962826-T-C
• rs7143875
• NM_018319.4:c.-7-282T>C

Your query was ambiguous. Multiple possible variants found:

• chr14-89962826-T-C
• chr14-89962826-T-G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_018319.4(TDP1):​c.-7-282T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0766 in 740,712 control chromosomes in the GnomAD database, including 7,591 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.17 (5343 hom., cov: 32)
  • Exomes 𝑓: 0.051 (2248 hom.)
• Consequence: TDP1 NM_018319.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.97
• Publications: 1 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: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
• 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BP6: Variant 14-89962826-T-C is Benign according to our data. Variant chr14-89962826-T-C is described in ClinVar as Benign. ClinVar VariationId is 1287106.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.486 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018319.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TDP1	NM_018319.4	MANE Select	c.-7-282T>C		intron	N/A	NP_060789.2
	TDP1	NM_001008744.2		c.-7-282T>C		intron	N/A	NP_001008744.1	Q9NUW8-1
	TDP1	NM_001330205.2		c.-7-282T>C		intron	N/A	NP_001317134.1	G3V2F4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TDP1	ENST00000335725.9	TSL:1 MANE Select	c.-7-282T>C		intron	N/A	ENSP00000337353.4	Q9NUW8-1
	TDP1	ENST00000393454.6	TSL:1	c.-7-282T>C		intron	N/A	ENSP00000377099.2	Q9NUW8-1
	TDP1	ENST00000393452.7	TSL:1	c.-7-282T>C		intron	N/A	ENSP00000377098.3	E7EPD8

Frequencies

GnomAD3 genomes AF: 0.174 AC: 26430 AN: 151814 Hom.: 5320 Cov.: 32

Gnomad AFR AF: 0.491

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.110

Gnomad ASJ AF: 0.108

Gnomad EAS AF: 0.0290

Gnomad SAS AF: 0.0961

Gnomad FIN AF: 0.0383

Gnomad MID AF: 0.108

Gnomad NFE AF: 0.0404

Gnomad OTH AF: 0.145

GnomAD4 exome AF: 0.0513 AC: 30225 AN: 588780 Hom.: 2248 AF XY: 0.0507 AC XY: 13980 AN XY: 275750

African (AFR) AF: 0.538 AC: 6091 AN: 11318

American (AMR) AF: 0.0775 AC: 53 AN: 684

Ashkenazi Jewish (ASJ) AF: 0.104 AC: 378 AN: 3620

East Asian (EAS) AF: 0.0296 AC: 76 AN: 2564

South Asian (SAS) AF: 0.0947 AC: 1101 AN: 11632

European-Finnish (FIN) AF: 0.0319 AC: 6 AN: 188

Middle Eastern (MID) AF: 0.112 AC: 132 AN: 1174

European-Non Finnish (NFE) AF: 0.0389 AC: 20950 AN: 538364

Other (OTH) AF: 0.0748 AC: 1438 AN: 19236

GnomAD4 genome AF: 0.174 AC: 26507 AN: 151932 Hom.: 5343 Cov.: 32 AF XY: 0.169 AC XY: 12517 AN XY: 74262

African (AFR) AF: 0.491 AC: 20339 AN: 41388

American (AMR) AF: 0.110 AC: 1683 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.108 AC: 375 AN: 3470

East Asian (EAS) AF: 0.0290 AC: 150 AN: 5166

South Asian (SAS) AF: 0.0960 AC: 461 AN: 4804

European-Finnish (FIN) AF: 0.0383 AC: 405 AN: 10564

Middle Eastern (MID) AF: 0.112 AC: 33 AN: 294

European-Non Finnish (NFE) AF: 0.0404 AC: 2748 AN: 67950

Other (OTH) AF: 0.147 AC: 310 AN: 2110

Alfa AF: 0.0389 Hom.: 94

Bravo AF: 0.194

Asia WGS AF: 0.0940 AC: 330 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.35
DANN	Benign	0.59
PhyloP100		-2.0
PromoterAI		0.027	Neutral
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: rs7143875; hg19: chr14-90429170;