Genetic Variant NM_001067.4:c.4543G>T (chr17-40389572-C-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001067.4(TOP2A):c.4543G>T(p.Ala1515Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0249 in 1,602,550 control chromosomes in the GnomAD database, including 663 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.037 ( 171 hom., cov: 32)

Exomes 𝑓: 0.024 ( 492 hom. )

Consequence

TOP2A
NM_001067.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.174

Publications

17 publications found

Variant links:

Genes affected

TOP2A (HGNC:11989): (DNA topoisomerase II alpha) This gene encodes a DNA topoisomerase, an enzyme that controls and alters the topologic states of DNA during transcription. This nuclear enzyme is involved in processes such as chromosome condensation, chromatid separation, and the relief of torsional stress that occurs during DNA transcription and replication. It catalyzes the transient breaking and rejoining of two strands of duplex DNA which allows the strands to pass through one another, thus altering the topology of DNA. Two forms of this enzyme exist as likely products of a gene duplication event. The gene encoding this form, alpha, is localized to chromosome 17 and the beta gene is localized to chromosome 3. The gene encoding this enzyme functions as the target for several anticancer agents and a variety of mutations in this gene have been associated with the development of drug resistance. Reduced activity of this enzyme may also play a role in ataxia-telangiectasia. [provided by RefSeq, Jul 2010]

TOP2A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0026789904).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0744 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TOP2A	NM_001067.4 link	c.4543G>T	p.Ala1515Ser	missense_variant	Exon 35 of 35	ENST00000423485.6	NP_001058.2	P11388-1
TOP2A	XM_005257632.2 link	c.4507G>T	p.Ala1503Ser	missense_variant	Exon 35 of 35		XP_005257689.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TOP2A	ENST00000423485.6 link	c.4543G>T	p.Ala1515Ser	missense_variant	Exon 35 of 35	1	NM_001067.4	ENSP00000411532.1	P11388-1
TOP2A	ENST00000577541.1 link	c.31G>T	p.Ala11Ser	missense_variant	Exon 1 of 2	2		ENSP00000464055.1	J3QR57
TOP2A	ENST00000578412.1 link	n.872G>T		non_coding_transcript_exon_variant	Exon 3 of 3	2

Frequencies

GnomAD3 genomes

AF:

0.0370

AC:

5631

AN:

152078

Hom.:

167

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0762

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.0296

Gnomad ASJ

AF:

0.00952

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00663

Gnomad FIN

AF:

0.0228

Gnomad MID

AF:

0.0253

Gnomad NFE

AF:

0.0240

Gnomad OTH

AF:

0.0350

GnomAD2 exomes

AF:

0.0204

AC:

4715

AN:

230642

AF XY:

0.0189

show subpopulations

Gnomad AFR exome

AF:

0.0781

Gnomad AMR exome

AF:

0.0137

Gnomad ASJ exome

AF:

0.0114

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0236

Gnomad NFE exome

AF:

0.0220

Gnomad OTH exome

AF:

0.0226

GnomAD4 exome

AF:

0.0236

AC:

34264

AN:

1450354

Hom.:

492

Cov.:

AF XY:

0.0230

AC XY:

16553

AN XY:

720228

show subpopulations

African (AFR)

AF:

0.0767

AC:

2556

AN:

33320

American (AMR)

AF:

0.0148

AC:

635

AN:

43028

Ashkenazi Jewish (ASJ)

AF:

0.0113

AC:

291

AN:

25804

East Asian (EAS)

AF:

0.00

AC:

AN:

39514

South Asian (SAS)

AF:

0.00695

AC:

584

AN:

84058

European-Finnish (FIN)

AF:

0.0219

AC:

1157

AN:

52848

Middle Eastern (MID)

AF:

0.0471

AC:

271

AN:

5754

European-Non Finnish (NFE)

AF:

0.0246

AC:

27164

AN:

1106052

Other (OTH)

AF:

0.0268

AC:

1606

AN:

59976

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.456

Heterozygous variant carriers

1685

3369

5054

6738

8423

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1078

2156

3234

4312

5390

<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:

0.0372

AC:

5656

AN:

152196

Hom.:

171

Cov.:

AF XY:

0.0361

AC XY:

2687

AN XY:

74412

show subpopulations

African (AFR)

AF:

0.0766

AC:

3180

AN:

41504

American (AMR)

AF:

0.0295

AC:

451

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.00952

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00663

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.0228

AC:

242

AN:

10610

Middle Eastern (MID)

AF:

0.0272

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0241

AC:

1636

AN:

68018

Other (OTH)

AF:

0.0346

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

259

519

778

1038

1297

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

180

240

300

<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:

0.0283

Hom.:

175

Bravo

AF:

0.0391

TwinsUK

AF:

0.0264

AC:

ALSPAC

AF:

0.0257

AC:

ESP6500AA

AF:

0.0800

AC:

296

ESP6500EA

AF:

0.0221

AC:

181

ExAC

AF:

0.0197

AC:

2376

Asia WGS

AF:

0.0120

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.080

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.59

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.053

T;T

Eigen

Benign

-0.68

Eigen_PC

Benign

-0.69

FATHMM_MKL

Benign

0.085

LIST_S2

Benign

0.59

T;T

MetaRNN

Benign

0.0027

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.8

L;.

PhyloP100

0.17

PrimateAI

Benign

0.29

PROVEAN

Benign

-1.3

N;.

REVEL

Benign

0.065

Sift

Benign

0.11

T;.

Sift4G

Benign

0.14

T;T

Polyphen

0.0

B;.

Vest4

0.015

MPC

0.13

ClinPred

0.014

GERP RS

2.2

PromoterAI

-0.011

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.052

gMVP

0.088

Mutation Taster

=98/2

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

Computational scores

Splicing

Publications

Other links and lift over