14-89963399-G-T

Position:

chr14-89963399-G-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS1

The NM_018319.4(TDP1):c.285G>T(p.Glu95Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000455 in 1,614,212 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.0025 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00024 ( 1 hom. )

Consequence

TDP1
NM_018319.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.233

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:

TDP1 (HGNC:):

TDP1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.002392292).

BP6

Variant 14-89963399-G-T is Benign according to our data. Variant chr14-89963399-G-T is described in ClinVar as [Benign]. Clinvar id is 448655.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-89963399-G-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00254 (387/152350) while in subpopulation AFR AF= 0.00902 (375/41578). AF 95% confidence interval is 0.00827. There are 1 homozygotes in gnomad4. There are 180 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TDP1	NM_018319.4 linkuse as main transcript	c.285G>T	p.Glu95Asp	missense_variant	3/17	ENST00000335725.9	NP_060789.2	Q9NUW8-1A0A024R6L5B3KN41

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TDP1	ENST00000335725.9 linkuse as main transcript	c.285G>T	p.Glu95Asp	missense_variant	3/17	1	NM_018319.4	ENSP00000337353.4		Q9NUW8-1

Frequencies

GnomAD3 genomes

AF:

0.00254

AC:

387

AN:

152232

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00905

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000655

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:

0.0000147

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000648

AC:

163

AN:

251372

Hom.:

AF XY:

0.000368

AC XY:

AN XY:

135864

show subpopulations

Gnomad AFR exome

AF:

0.00911

Gnomad AMR exome

AF:

0.000376

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:

0.000326

GnomAD4 exome

AF:

0.000238

AC:

348

AN:

1461862

Hom.:

Cov.:

AF XY:

0.000173

AC XY:

126

AN XY:

727236

show subpopulations

Gnomad4 AFR exome

AF:

0.00884

Gnomad4 AMR exome

AF:

0.000313

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:

0.00000180

Gnomad4 OTH exome

AF:

0.000580

GnomAD4 genome

AF:

0.00254

AC:

387

AN:

152350

Hom.:

Cov.:

AF XY:

0.00242

AC XY:

180

AN XY:

74506

show subpopulations

Gnomad4 AFR

AF:

0.00902

Gnomad4 AMR

AF:

0.000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000350

Hom.:

Bravo

AF:

0.00309

ESP6500AA

AF:

0.0107

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000898

AC:

109

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 27, 2018	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

May 09, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.083

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.57

CADD

Benign

5.1

DANN

Uncertain

0.99

DEOGEN2

Benign

0.015

.;T;T;T;T;T;T;.;.

Eigen

Benign

-0.62

Eigen_PC

Benign

-0.63

FATHMM_MKL

Benign

0.29

LIST_S2

Benign

0.71

T;T;.;T;T;T;T;T;T

MetaRNN

Benign

0.0024

T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.5

.;.;M;M;.;.;.;.;.

PrimateAI

Benign

0.40

PROVEAN

Benign

-0.98

N;N;N;N;N;N;N;N;N

REVEL

Benign

0.066

Sift

Benign

0.15

T;T;T;T;T;T;T;T;T

Sift4G

Benign

0.17

T;T;T;T;T;T;T;T;T

Polyphen

0.073

B;.;B;B;.;.;.;.;B

Vest4

0.20

MutPred

0.076

Loss of helix (P = 0.2662);Loss of helix (P = 0.2662);Loss of helix (P = 0.2662);Loss of helix (P = 0.2662);Loss of helix (P = 0.2662);Loss of helix (P = 0.2662);Loss of helix (P = 0.2662);Loss of helix (P = 0.2662);Loss of helix (P = 0.2662);

MVP

0.36

MPC

0.12

ClinPred

0.014

GERP RS

2.4

Varity_R

0.047

gMVP

0.084

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

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over