Variant chr14-89967384-C-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_018319.4(TDP1):c.621C>A(p.Asp207Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000496 in 1,613,922 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. D207D) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

TDP1
NM_018319.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.67

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 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.848

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TDP1	NM_018319.4 linkuse as main transcript	c.621C>A	p.Asp207Glu	missense_variant	5/17	ENST00000335725.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TDP1	ENST00000335725.9 linkuse as main transcript	c.621C>A	p.Asp207Glu	missense_variant	5/17	1	NM_018319.4	P1	Q9NUW8-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000795

AC:

AN:

251484

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135920

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000342

AC:

AN:

1461748

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727182

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152174

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74354

show subpopulations

Gnomad4 AFR

AF:

0.0000724

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000604

ExAC

AF:

0.00000824

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Uncertain

0.070

BayesDel_noAF

Uncertain

0.10

CADD

Benign

0.078

DANN

Benign

0.87

DEOGEN2

Benign

0.20

.;T;T;.;T;.

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.13

LIST_S2

Uncertain

0.86

D;D;.;D;D;D

M_CAP

Benign

0.033

MetaRNN

Pathogenic

0.85

D;D;D;D;D;D

MetaSVM

Uncertain

-0.15

MutationAssessor

Uncertain

2.8

.;.;M;.;M;.

MutationTaster

Benign

1.0

D;D;D;D;D

PrimateAI

Uncertain

0.60

PROVEAN

Uncertain

-3.3

D;D;D;D;D;D

REVEL

Uncertain

0.42

Sift

Benign

0.080

T;D;D;D;D;D

Sift4G

Uncertain

0.010

D;D;D;D;D;D

Polyphen

0.76

P;.;P;.;P;P

Vest4

0.74

MutPred

0.81

Loss of sheet (P = 0.1501);Loss of sheet (P = 0.1501);Loss of sheet (P = 0.1501);.;Loss of sheet (P = 0.1501);Loss of sheet (P = 0.1501);

MVP

0.19

MPC

0.18

ClinPred

0.69

GERP RS

-12

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.7

Varity_R

0.64

gMVP

0.86

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over