Genetic Variant TDP1:c.-230-14C>A (chr14-89956564-C-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_018319.4(TDP1):c.-230-14C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.251 in 152,240 control chromosomes in the GnomAD database, including 8,005 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.25 ( 8002 hom., cov: 33)

Exomes 𝑓: 0.13 ( 3 hom. )

Consequence

TDP1
NM_018319.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -1.59

Publications

7 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: 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

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 (BayesDel_noAF=-0.77).

BP6

Variant 14-89956564-C-A is Benign according to our data. Variant chr14-89956564-C-A is described in ClinVar as Benign. ClinVar VariationId is 314815.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.558 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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
TDP1	NM_018319.4	MANE Select	c.-230-14C>A	intron	N/A	NP_060789.2
TDP1	NM_001008744.2		c.-8+594C>A	intron	N/A	NP_001008744.1	Q9NUW8-1
TDP1	NM_001330205.2		c.-8+286C>A	intron	N/A	NP_001317134.1	G3V2F4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
TDP1	ENST00000335725.9	TSL:1 MANE Select	c.-230-14C>A	intron	N/A	ENSP00000337353.4	Q9NUW8-1
TDP1	ENST00000393454.6	TSL:1	c.-8+594C>A	intron	N/A	ENSP00000377099.2	Q9NUW8-1
TDP1	ENST00000393452.7	TSL:1	c.-230-14C>A	intron	N/A	ENSP00000377098.3	E7EPD8

Frequencies

GnomAD3 genomes

AF:

0.251

AC:

38168

AN:

151964

Hom.:

7976

Cov.:

show subpopulations

Gnomad AFR

AF:

0.564

Gnomad AMI

AF:

0.0285

Gnomad AMR

AF:

0.284

Gnomad ASJ

AF:

0.153

Gnomad EAS

AF:

0.224

Gnomad SAS

AF:

0.294

Gnomad FIN

AF:

0.101

Gnomad MID

AF:

0.146

Gnomad NFE

AF:

0.0856

Gnomad OTH

AF:

0.212

GnomAD4 exome

AF:

0.131

AC:

AN:

160

Hom.:

Cov.:

AF XY:

0.115

AC XY:

AN XY:

122

show subpopulations

African (AFR)

AF:

0.500

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

East Asian (EAS)

AF:

0.250

AC:

AN:

South Asian (SAS)

AF:

0.00

AC:

AN:

European-Finnish (FIN)

AF:

0.125

AC:

AN:

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.117

AC:

AN:

128

Other (OTH)

AF:

0.250

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome 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

GnomAD4 genome

AF:

0.252

AC:

38259

AN:

152080

Hom.:

8002

Cov.:

AF XY:

0.254

AC XY:

18904

AN XY:

74366

show subpopulations

African (AFR)

AF:

0.564

AC:

23373

AN:

41430

American (AMR)

AF:

0.285

AC:

4358

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.153

AC:

530

AN:

3470

East Asian (EAS)

AF:

0.224

AC:

1155

AN:

5158

South Asian (SAS)

AF:

0.294

AC:

1416

AN:

4818

European-Finnish (FIN)

AF:

0.101

AC:

1073

AN:

10606

Middle Eastern (MID)

AF:

0.153

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0856

AC:

5823

AN:

68000

Other (OTH)

AF:

0.218

AC:

460

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

1136

2272

3408

4544

5680

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

352

704

1056

1408

1760

<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:

0.195

Hom.:

699

Bravo

AF:

0.278

Asia WGS

AF:

0.306

AC:

1065

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

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

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.77

CADD

Benign

1.3

(source)

DANN

Benign

0.60

PhyloP100

-1.6

PromoterAI

-0.0096

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over