rs201355368

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBS1_Supporting

The NM_018319.4(TDP1):c.1747A>G(p.Ser583Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000241 in 1,582,244 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00037 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00023 ( 0 hom. )

Consequence

TDP1
NM_018319.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 1.83

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.015897483).

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000368 (56/152248) while in subpopulation NFE AF= 0.000471 (32/68008). AF 95% confidence interval is 0.000342. There are 0 homozygotes in gnomad4. There are 28 alleles in male gnomad4 subpopulation. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TDP1	NM_018319.4 linkuse as main transcript	c.1747A>G	p.Ser583Gly	missense_variant	16/17	ENST00000335725.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TDP1	ENST00000335725.9 linkuse as main transcript	c.1747A>G	p.Ser583Gly	missense_variant	16/17	1	NM_018319.4	P1	Q9NUW8-1

Frequencies

GnomAD3 genomes

AF:

0.000368

AC:

AN:

152130

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.00226

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000470

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000351

AC:

AN:

250966

Hom.:

AF XY:

0.000347

AC XY:

AN XY:

135626

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00180

Gnomad NFE exome

AF:

0.000414

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.000227

AC:

325

AN:

1429996

Hom.:

Cov.:

AF XY:

0.000240

AC XY:

171

AN XY:

713334

show subpopulations

Gnomad4 AFR exome

AF:

0.00

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:

0.00217

Gnomad4 NFE exome

AF:

0.000178

Gnomad4 OTH exome

AF:

0.000253

GnomAD4 genome

AF:

0.000368

AC:

AN:

152248

Hom.:

Cov.:

AF XY:

0.000376

AC XY:

AN XY:

74458

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00226

Gnomad4 NFE

AF:

0.000471

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000232

Hom.:

Bravo

AF:

0.000106

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000387

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Athena Diagnostics

Apr 27, 2017

- -

Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.43

Cadd

Uncertain

Dann

Uncertain

1.0

DEOGEN2

Benign

0.25

T;T

Eigen

Benign

-0.47

Eigen_PC

Benign

-0.39

FATHMM_MKL

Benign

0.29

M_CAP

Benign

0.012

MetaRNN

Benign

0.016

T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

1.8

L;L

MutationTaster

Benign

0.98

N;N;N;N;N

PrimateAI

Benign

0.37

PROVEAN

Benign

-1.8

N;N

REVEL

Benign

0.055

Sift

Benign

0.11

T;T

Sift4G

Benign

0.55

T;T

Polyphen

0.0010

B;B

Vest4

0.23

MVP

0.67

MPC

0.099

ClinPred

0.032

GERP RS

1.8

Varity_R

0.20

gMVP

0.19

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.59

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.59

Position offset: 0

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