dbSNP rs2293925: TOP1MT:p.Arg525Trp (chr8-143310198-G-A) – ACMG Classification: Benign (-20 pts)

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.1573C>T(p.Arg525Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.449 in 1,579,896 control chromosomes in the GnomAD database, including 169,713 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.38 ( 13454 hom., cov: 33)

Exomes 𝑓: 0.46 ( 156259 hom. )

Consequence

TOP1MT
NM_052963.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.176

Publications

41 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=4.9609944E-6).

BP6

Variant 8-143310198-G-A is Benign according to our data. Variant chr8-143310198-G-A is described in ClinVar as Benign. ClinVar VariationId is 1645532.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.664 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TOP1MT	NM_052963.3 link	c.1573C>T	p.Arg525Trp	missense_variant	Exon 13 of 14	ENST00000329245.9	NP_443195.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TOP1MT	ENST00000329245.9 link	c.1573C>T	p.Arg525Trp	missense_variant	Exon 13 of 14	1	NM_052963.3	ENSP00000328835.3

Frequencies

GnomAD3 genomes

AF:

0.376

AC:

57154

AN:

151956

Hom.:

13436

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0975

Gnomad AMI

AF:

0.467

Gnomad AMR

AF:

0.556

Gnomad ASJ

AF:

0.346

Gnomad EAS

AF:

0.683

Gnomad SAS

AF:

0.636

Gnomad FIN

AF:

0.523

Gnomad MID

AF:

0.301

Gnomad NFE

AF:

0.441

Gnomad OTH

AF:

0.387

GnomAD2 exomes

AF:

0.505

AC:

107399

AN:

212494

AF XY:

0.511

show subpopulations

Gnomad AFR exome

AF:

0.0907

Gnomad AMR exome

AF:

0.682

Gnomad ASJ exome

AF:

0.362

Gnomad EAS exome

AF:

0.708

Gnomad FIN exome

AF:

0.537

Gnomad NFE exome

AF:

0.446

Gnomad OTH exome

AF:

0.471

GnomAD4 exome

AF:

0.457

AC:

652480

AN:

1427822

Hom.:

156259

Cov.:

AF XY:

0.462

AC XY:

326913

AN XY:

707740

show subpopulations

African (AFR)

AF:

0.0806

AC:

2621

AN:

32512

American (AMR)

AF:

0.661

AC:

26633

AN:

40300

Ashkenazi Jewish (ASJ)

AF:

0.343

AC:

8430

AN:

24558

East Asian (EAS)

AF:

0.704

AC:

27398

AN:

38892

South Asian (SAS)

AF:

0.627

AC:

52153

AN:

83142

European-Finnish (FIN)

AF:

0.528

AC:

26104

AN:

49406

Middle Eastern (MID)

AF:

0.373

AC:

1913

AN:

5126

European-Non Finnish (NFE)

AF:

0.440

AC:

481337

AN:

1095096

Other (OTH)

AF:

0.440

AC:

25891

AN:

58790

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

16508

33017

49525

66034

82542

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

14802

29604

44406

59208

74010

<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:

0.376

AC:

57188

AN:

152074

Hom.:

13454

Cov.:

AF XY:

0.389

AC XY:

28937

AN XY:

74340

show subpopulations

African (AFR)

AF:

0.0973

AC:

4039

AN:

41516

American (AMR)

AF:

0.557

AC:

8511

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.346

AC:

1202

AN:

3472

East Asian (EAS)

AF:

0.683

AC:

3510

AN:

5138

South Asian (SAS)

AF:

0.635

AC:

3068

AN:

4828

European-Finnish (FIN)

AF:

0.523

AC:

5538

AN:

10582

Middle Eastern (MID)

AF:

0.310

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.441

AC:

29984

AN:

67946

Other (OTH)

AF:

0.390

AC:

822

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1628

3256

4885

6513

8141

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

548

1096

1644

2192

2740

<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:

0.433

Hom.:

22280

Bravo

AF:

0.364

TwinsUK

AF:

0.430

AC:

1593

ALSPAC

AF:

0.450

AC:

1734

ESP6500AA

AF:

0.0987

AC:

434

ESP6500EA

AF:

0.441

AC:

3794

ExAC

AF:

0.470

AC:

56544

Asia WGS

AF:

0.610

AC:

2123

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.43

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.35

T;.;.;.

Eigen

Benign

-0.26

Eigen_PC

Benign

-0.48

FATHMM_MKL

Benign

0.28

LIST_S2

Uncertain

0.89

D;.;.;D

MetaRNN

Benign

0.0000050

T;T;T;T

MetaSVM

Benign

-0.94

MutationAssessor

Uncertain

2.3

M;.;.;.

PhyloP100

0.18

PrimateAI

Benign

0.36

PROVEAN

Uncertain

-4.3

D;D;D;D

REVEL

Benign

0.14

Sift

Uncertain

0.019

D;D;D;D

Sift4G

Uncertain

0.0020

D;D;D;D

Polyphen

0.99

D;.;.;.

Vest4

0.12

MPC

0.19

ClinPred

0.043

GERP RS

-3.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.3

Varity_R

0.12

gMVP

0.24

Mutation Taster

=100/0

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