dbSNP rs35973343: TDP1:p.Thr569Ala (chr14-90033166-A-G) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_018319.4(TDP1):c.1705A>G(p.Thr569Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000796 in 1,613,552 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0038 ( 2 hom., cov: 32)

Exomes 𝑓: 0.00048 ( 4 hom. )

Consequence

TDP1
NM_018319.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.0870

Publications

1 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, MODERATE, SUPPORTIVE, LIMITED Submitted by: Orphanet, PanelApp Australia, 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.002592653).

BP6

Variant 14-90033166-A-G is Benign according to our data. Variant chr14-90033166-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 314839.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAdExome4 allele frequency = 0.00048 (702/1461350) while in subpopulation AFR AF = 0.0169 (565/33470). AF 95% confidence interval is 0.0157. There are 4 homozygotes in GnomAdExome4. There are 315 alleles in the male GnomAdExome4 subpopulation. Median coverage is 29. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TDP1	NM_018319.4	MANE Select	c.1705A>G	p.Thr569Ala	missense	Exon 16 of 17	NP_060789.2
TDP1	NM_001008744.2		c.1705A>G	p.Thr569Ala	missense	Exon 15 of 16	NP_001008744.1	Q9NUW8-1
TDP1	NM_001330205.2		c.1645-9904A>G		intron	N/A	NP_001317134.1	G3V2F4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TDP1	ENST00000335725.9	TSL:1 MANE Select	c.1705A>G	p.Thr569Ala	missense	Exon 16 of 17	ENSP00000337353.4	Q9NUW8-1
TDP1	ENST00000393454.6	TSL:1	c.1705A>G	p.Thr569Ala	missense	Exon 15 of 16	ENSP00000377099.2	Q9NUW8-1
TDP1	ENST00000393452.7	TSL:1	c.1751A>G	p.His584Arg	missense	Exon 17 of 18	ENSP00000377098.3	E7EPD8

Frequencies

GnomAD3 genomes

AF:

0.00379

AC:

577

AN:

152084

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0135

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000524

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00383

GnomAD2 exomes

AF:

0.00111

AC:

280

AN:

251326

AF XY:

0.000729

show subpopulations

Gnomad AFR exome

AF:

0.0153

Gnomad AMR exome

AF:

0.000521

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000792

Gnomad OTH exome

AF:

0.000489

GnomAD4 exome

AF:

0.000480

AC:

702

AN:

1461350

Hom.:

Cov.:

AF XY:

0.000433

AC XY:

315

AN XY:

727044

show subpopulations

African (AFR)

AF:

0.0169

AC:

565

AN:

33470

American (AMR)

AF:

0.000649

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26128

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000696

AC:

AN:

86234

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53410

Middle Eastern (MID)

AF:

0.00156

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0000144

AC:

AN:

1111546

Other (OTH)

AF:

0.00128

AC:

AN:

60378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

130

163

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.00382

AC:

582

AN:

152202

Hom.:

Cov.:

AF XY:

0.00377

AC XY:

281

AN XY:

74442

show subpopulations

African (AFR)

AF:

0.0135

AC:

562

AN:

41518

American (AMR)

AF:

0.000523

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3464

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000588

AC:

AN:

68000

Other (OTH)

AF:

0.00379

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

105

131

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.00170

Hom.:

Bravo

AF:

0.00470

ESP6500AA

AF:

0.0134

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00137

AC:

166

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

not specified (2)

Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 1 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.051

BayesDel_addAF

Benign

-0.64

BayesDel_noAF

Benign

-0.48

CADD

Benign

6.6

(source)

DANN

Benign

0.36

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.024

LIST_S2

Benign

0.38

MetaRNN

Benign

0.0026

MetaSVM

Benign

-0.99

PhyloP100

0.087

PROVEAN

Benign

-0.46

REVEL

Benign

0.060

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

0.0

Vest4

0.14

MVP

0.072

ClinPred

0.00094

GERP RS

-7.5

Varity_R

0.11

Mutation Taster

=95/5

polymorphism

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over