8-143324535-C-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -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. 14/20 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 0.33 ( 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

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 made for transcript

Verdict is Benign. Variant got -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 id 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

GnomAD3 exomes

AF:

0.263

AC:

65997

AN:

251280

Hom.:

9965

AF XY:

0.262

AC XY:

35599

AN XY:

135856

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 SAS exome

AF:

0.218

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

Gnomad4 AFR exome

AF:

0.497

Gnomad4 AMR exome

AF:

0.179

Gnomad4 ASJ exome

AF:

0.274

Gnomad4 EAS exome

AF:

0.0670

Gnomad4 SAS exome

AF:

0.221

Gnomad4 FIN exome

AF:

0.288

Gnomad4 NFE exome

AF:

0.291

Gnomad4 OTH exome

AF:

0.286

GnomAD4 genome

AF:

0.327

AC:

49665

AN:

152088

Hom.:

9016

Cov.:

AF XY:

0.321

AC XY:

23849

AN XY:

74350

show subpopulations

Gnomad4 AFR

AF:

0.485

Gnomad4 AMR

AF:

0.226

Gnomad4 ASJ

AF:

0.262

Gnomad4 EAS

AF:

0.0742

Gnomad4 SAS

AF:

0.210

Gnomad4 FIN

AF:

0.289

Gnomad4 NFE

AF:

0.289

Gnomad4 OTH

AF:

0.328

Alfa

AF:

0.294

Hom.:

10082

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

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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) -

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

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;.;.;.;.;.;.

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

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