chr8-143324535-C-T

Variant names:

Variant summary

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

The NM_052963.3(TOP1MT):c.766G>A(p.Val256Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.286 in 1,613,628 control chromosomes in the GnomAD database, including 70,245 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.33 ( 9016 hom., cov: 33)

Exomes 𝑓: 0.28 ( 61229 hom. )

Consequence

TOP1MT
NM_052963.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.44

Publications

43 publications found

Variant links:

Genes affected

TOP1MT (HGNC:29787): (DNA topoisomerase I mitochondrial) This gene encodes a mitochondrial DNA topoisomerase that plays a role in the modification of DNA topology. The encoded protein is a type IB topoisomerase and catalyzes the transient breaking and rejoining of DNA to relieve tension and DNA supercoiling generated in the mitochondrial genome during replication and transcription. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, May 2012]

TOP1MT 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 (MetaRNN=7.775426E-4).

BP6

Variant 8-143324535-C-T is Benign according to our data. Variant chr8-143324535-C-T is described in ClinVar as Benign. ClinVar VariationId is 1251430.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.479 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TOP1MT	NM_052963.3 link	c.766G>A	p.Val256Ile	missense_variant	Exon 6 of 14	ENST00000329245.9	NP_443195.1	Q969P6-1E5KMK7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TOP1MT	ENST00000329245.9 link	c.766G>A	p.Val256Ile	missense_variant	Exon 6 of 14	1	NM_052963.3	ENSP00000328835.3		Q969P6-1

Frequencies

GnomAD3 genomes

AF:

0.327

AC:

49624

AN:

151970

Hom.:

9002

Cov.:

show subpopulations

Gnomad AFR

AF:

0.485

Gnomad AMI

AF:

0.314

Gnomad AMR

AF:

0.227

Gnomad ASJ

AF:

0.262

Gnomad EAS

AF:

0.0744

Gnomad SAS

AF:

0.209

Gnomad FIN

AF:

0.289

Gnomad MID

AF:

0.354

Gnomad NFE

AF:

0.289

Gnomad OTH

AF:

0.330

GnomAD2 exomes

AF:

0.263

AC:

65997

AN:

251280

AF XY:

0.262

show subpopulations

Gnomad AFR exome

AF:

0.488

Gnomad AMR exome

AF:

0.171

Gnomad ASJ exome

AF:

0.274

Gnomad EAS exome

AF:

0.0669

Gnomad FIN exome

AF:

0.285

Gnomad NFE exome

AF:

0.296

Gnomad OTH exome

AF:

0.277

GnomAD4 exome

AF:

0.282

AC:

412146

AN:

1461540

Hom.:

61229

Cov.:

AF XY:

0.281

AC XY:

204049

AN XY:

727084

show subpopulations

African (AFR)

AF:

0.497

AC:

16634

AN:

33478

American (AMR)

AF:

0.179

AC:

7997

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.274

AC:

7154

AN:

26136

East Asian (EAS)

AF:

0.0670

AC:

2660

AN:

39698

South Asian (SAS)

AF:

0.221

AC:

19086

AN:

86258

European-Finnish (FIN)

AF:

0.288

AC:

15330

AN:

53142

Middle Eastern (MID)

AF:

0.341

AC:

1968

AN:

5766

European-Non Finnish (NFE)

AF:

0.291

AC:

324029

AN:

1111958

Other (OTH)

AF:

0.286

AC:

17288

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

17375

34750

52126

69501

86876

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

10602

21204

31806

42408

53010

<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:

0.327

AC:

49665

AN:

152088

Hom.:

9016

Cov.:

AF XY:

0.321

AC XY:

23849

AN XY:

74350

show subpopulations

African (AFR)

AF:

0.485

AC:

20103

AN:

41466

American (AMR)

AF:

0.226

AC:

3460

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.262

AC:

911

AN:

3472

East Asian (EAS)

AF:

0.0742

AC:

384

AN:

5178

South Asian (SAS)

AF:

0.210

AC:

1011

AN:

4822

European-Finnish (FIN)

AF:

0.289

AC:

3063

AN:

10594

Middle Eastern (MID)

AF:

0.347

AC:

102

AN:

294

European-Non Finnish (NFE)

AF:

0.289

AC:

19655

AN:

67966

Other (OTH)

AF:

0.328

AC:

690

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1668

3336

5004

6672

8340

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

468

936

1404

1872

2340

<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:

0.299

Hom.:

22727

Bravo

AF:

0.329

TwinsUK

AF:

0.293

AC:

1088

ALSPAC

AF:

0.292

AC:

1124

ESP6500AA

AF:

0.495

AC:

2179

ESP6500EA

AF:

0.282

AC:

2426

ExAC

AF:

0.270

AC:

32817

Asia WGS

AF:

0.176

AC:

612

AN:

3478

EpiCase

AF:

0.297

EpiControl

AF:

0.290

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Aug 23, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 28819183) -

Feb 03, 2025

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

0.065

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.57

CADD

Benign

0.87

(source)

DANN

Benign

0.37

DEOGEN2

Benign

0.057

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

Eigen

Benign

-1.8

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.24

LIST_S2

Benign

0.62

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

MetaRNN

Benign

0.00078

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

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.91

N;.;.;.;.;.;.

PhyloP100

1.4

PrimateAI

Benign

0.39

PROVEAN

Benign

0.35

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

REVEL

Benign

0.071

Sift

Benign

1.0

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

Sift4G

Benign

1.0

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

Polyphen

0.010

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

Vest4

0.032

MPC

0.16

ClinPred

0.0021

GERP RS

-7.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.011

gMVP

0.085

Mutation Taster

=99/1

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over