14-89963405-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_018319.4(TDP1):c.291A>G(p.Gln97Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0814 in 1,614,036 control chromosomes in the GnomAD database, including 22,814 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.24 ( 10970 hom., cov: 32)

Exomes 𝑓: 0.065 ( 11844 hom. )

Consequence

TDP1
NM_018319.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -2.46

Publications

19 publications found

Variant links:

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

TDP1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.88).

BP6

Variant 14-89963405-A-G is Benign according to our data. Variant chr14-89963405-A-G is described in ClinVar as Benign. ClinVar VariationId is 314824.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-2.46 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.704 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TDP1	NM_018319.4 link	c.291A>G	p.Gln97Gln	synonymous_variant	Exon 3 of 17	ENST00000335725.9	NP_060789.2	Q9NUW8-1A0A024R6L5B3KN41

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TDP1	ENST00000335725.9 link	c.291A>G	p.Gln97Gln	synonymous_variant	Exon 3 of 17	1	NM_018319.4	ENSP00000337353.4		Q9NUW8-1

Frequencies

GnomAD3 genomes

AF:

0.237

AC:

36118

AN:

152088

Hom.:

10932

Cov.:

show subpopulations

Gnomad AFR

AF:

0.711

Gnomad AMI

AF:

0.00329

Gnomad AMR

AF:

0.133

Gnomad ASJ

AF:

0.121

Gnomad EAS

AF:

0.0289

Gnomad SAS

AF:

0.104

Gnomad FIN

AF:

0.0386

Gnomad MID

AF:

0.133

Gnomad NFE

AF:

0.0413

Gnomad OTH

AF:

0.184

GnomAD2 exomes

AF:

0.104

AC:

26107

AN:

251322

AF XY:

0.0933

show subpopulations

Gnomad AFR exome

AF:

0.727

Gnomad AMR exome

AF:

0.0894

Gnomad ASJ exome

AF:

0.128

Gnomad EAS exome

AF:

0.0241

Gnomad FIN exome

AF:

0.0366

Gnomad NFE exome

AF:

0.0433

Gnomad OTH exome

AF:

0.0799

GnomAD4 exome

AF:

0.0651

AC:

95219

AN:

1461830

Hom.:

11844

Cov.:

AF XY:

0.0644

AC XY:

46848

AN XY:

727224

show subpopulations

African (AFR)

AF:

0.743

AC:

24880

AN:

33478

American (AMR)

AF:

0.0930

AC:

4160

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.128

AC:

3335

AN:

26126

East Asian (EAS)

AF:

0.0297

AC:

1181

AN:

39700

South Asian (SAS)

AF:

0.104

AC:

9011

AN:

86258

European-Finnish (FIN)

AF:

0.0390

AC:

2083

AN:

53418

Middle Eastern (MID)

AF:

0.148

AC:

854

AN:

5768

European-Non Finnish (NFE)

AF:

0.0393

AC:

43702

AN:

1111964

Other (OTH)

AF:

0.0996

AC:

6013

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

4453

8906

13358

17811

22264

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1992

3984

5976

7968

9960

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.238

AC:

36220

AN:

152206

Hom.:

10970

Cov.:

AF XY:

0.230

AC XY:

17126

AN XY:

74442

show subpopulations

African (AFR)

AF:

0.711

AC:

29468

AN:

41454

American (AMR)

AF:

0.132

AC:

2028

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.121

AC:

421

AN:

3472

East Asian (EAS)

AF:

0.0289

AC:

150

AN:

5182

South Asian (SAS)

AF:

0.103

AC:

499

AN:

4826

European-Finnish (FIN)

AF:

0.0386

AC:

410

AN:

10622

Middle Eastern (MID)

AF:

0.139

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0413

AC:

2808

AN:

68024

Other (OTH)

AF:

0.185

AC:

392

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

738

1476

2215

2953

3691

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

278

556

834

1112

1390

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.108

Hom.:

11594

Bravo

AF:

0.265

Asia WGS

AF:

0.119

AC:

417

AN:

3478

EpiCase

AF:

0.0487

EpiControl

AF:

0.0471

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Apr 13, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 1

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

-0.88

CADD

Benign

0.058

(source)

DANN

Benign

0.30

PhyloP100

-2.5

PromoterAI

-0.0068

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over