Genetic Variant TDP2:p.Ile307Val (chr6-24650958-T-C) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_016614.3(TDP2):c.919A>G(p.Ile307Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000809 in 1,614,160 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.0032 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00056 ( 6 hom. )

Consequence

TDP2
NM_016614.3 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 2.86

Variant links:

Genes affected

TDP2 (HGNC:17768): (tyrosyl-DNA phosphodiesterase 2) This gene encodes a member of a superfamily of divalent cation-dependent phosphodiesterases. The encoded protein associates with CD40, tumor necrosis factor (TNF) receptor-75 and TNF receptor associated factors (TRAFs), and inhibits nuclear factor-kappa-B activation. This protein has sequence and structural similarities with APE1 endonuclease, which is involved in both DNA repair and the activation of transcription factors. [provided by RefSeq, Jul 2008]

TDP2 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0033581257).

BP6

Variant 6-24650958-T-C is Benign according to our data. Variant chr6-24650958-T-C is described in ClinVar as [Benign]. Clinvar id is 718735.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-24650958-T-C is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00318 (484/152306) while in subpopulation AFR AF= 0.0102 (425/41576). AF 95% confidence interval is 0.00942. There are 0 homozygotes in gnomad4. There are 217 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TDP2	NM_016614.3 link	c.919A>G	p.Ile307Val	missense_variant	Exon 7 of 7	ENST00000378198.9	NP_057698.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TDP2	ENST00000378198.9 link	c.919A>G	p.Ile307Val	missense_variant	Exon 7 of 7	1	NM_016614.3	ENSP00000367440.4	O95551-1
TDP2	ENST00000341060.3 link	c.745A>G	p.Ile249Val	missense_variant	Exon 6 of 6	1		ENSP00000345345.3	X6R5A3
TDP2	ENST00000478507.1 link	n.*29A>G		downstream_gene_variant		5

Frequencies

GnomAD3 genomes

AF:

0.00317

AC:

482

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0102

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00216

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000279

Gnomad OTH

AF:

0.00239

GnomAD3 exomes

AF:

0.00119

AC:

299

AN:

251448

Hom.:

AF XY:

0.000942

AC XY:

128

AN XY:

135892

show subpopulations

Gnomad AFR exome

AF:

0.0121

Gnomad AMR exome

AF:

0.00121

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000555

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000361

Gnomad OTH exome

AF:

0.000489

GnomAD4 exome

AF:

0.000562

AC:

822

AN:

1461854

Hom.:

Cov.:

AF XY:

0.000549

AC XY:

399

AN XY:

727226

show subpopulations

Gnomad4 AFR exome

AF:

0.0105

Gnomad4 AMR exome

AF:

0.00121

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000452

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.000271

Gnomad4 OTH exome

AF:

0.000977

GnomAD4 genome

AF:

0.00318

AC:

484

AN:

152306

Hom.:

Cov.:

AF XY:

0.00291

AC XY:

217

AN XY:

74480

show subpopulations

Gnomad4 AFR

AF:

0.0102

Gnomad4 AMR

AF:

0.00216

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000208

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000279

Gnomad4 OTH

AF:

0.00237

Alfa

AF:

0.000635

Hom.:

Bravo

AF:

0.00364

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00862

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00139

AC:

169

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000709

EpiControl

AF:

0.000593

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.26

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.44

CADD

Benign

DANN

Benign

0.94

DEOGEN2

Benign

0.087

T;T

Eigen

Benign

-0.61

Eigen_PC

Benign

-0.47

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.70

T;T

MetaRNN

Benign

0.0034

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.39

N;.

PrimateAI

Benign

0.39

PROVEAN

Benign

0.010

N;N

REVEL

Benign

0.20

Sift

Benign

0.45

T;T

Sift4G

Benign

0.82

T;T

Polyphen

0.014

B;.

Vest4

0.049

MVP

0.79

MPC

0.19

ClinPred

0.014

GERP RS

4.9

Varity_R

0.080

gMVP

0.46

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