dbSNP rs13695: TOP2A:c.*578G>A (chr17-40388941-C-T) – 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.*578G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.185 in 207,890 control chromosomes in the GnomAD database, including 4,636 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.18 ( 3183 hom., cov: 32)

Exomes 𝑓: 0.20 ( 1453 hom. )

Consequence

TOP2A
NM_001067.4 3_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.77

Publications

25 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:

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ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.88).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.261 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TOP2A	NM_001067.4 link	c.*578G>A		3_prime_UTR_variant	Exon 35 of 35	ENST00000423485.6	NP_001058.2
TOP2A	XM_005257632.2 link	c.*578G>A		3_prime_UTR_variant	Exon 35 of 35		XP_005257689.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TOP2A	ENST00000423485.6 link	c.*578G>A		3_prime_UTR_variant	Exon 35 of 35	1	NM_001067.4	ENSP00000411532.1
TOP2A	ENST00000577541.1 link	c.*4-83G>A		intron_variant	Intron 1 of 1	2		ENSP00000464055.1

Frequencies

GnomAD3 genomes

AF:

0.180

AC:

27279

AN:

151946

Hom.:

3184

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0648

Gnomad AMI

AF:

0.184

Gnomad AMR

AF:

0.152

Gnomad ASJ

AF:

0.293

Gnomad EAS

AF:

0.00307

Gnomad SAS

AF:

0.110

Gnomad FIN

AF:

0.199

Gnomad MID

AF:

0.256

Gnomad NFE

AF:

0.264

Gnomad OTH

AF:

0.193

GnomAD4 exome

AF:

0.200

AC:

11181

AN:

55826

Hom.:

1453

Cov.:

AF XY:

0.201

AC XY:

5192

AN XY:

25780

show subpopulations

African (AFR)

AF:

0.0640

AC:

162

AN:

2532

American (AMR)

AF:

0.146

AC:

237

AN:

1628

Ashkenazi Jewish (ASJ)

AF:

0.270

AC:

965

AN:

3578

East Asian (EAS)

AF:

0.000236

AC:

AN:

8486

South Asian (SAS)

AF:

0.0796

AC:

AN:

490

European-Finnish (FIN)

AF:

0.210

AC:

101

AN:

480

Middle Eastern (MID)

AF:

0.214

AC:

AN:

322

European-Non Finnish (NFE)

AF:

0.255

AC:

8604

AN:

33696

Other (OTH)

AF:

0.217

AC:

1002

AN:

4614

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

413

826

1238

1651

2064

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.179

AC:

27270

AN:

152064

Hom.:

3183

Cov.:

AF XY:

0.173

AC XY:

12873

AN XY:

74346

show subpopulations

African (AFR)

AF:

0.0646

AC:

2682

AN:

41498

American (AMR)

AF:

0.152

AC:

2325

AN:

15260

Ashkenazi Jewish (ASJ)

AF:

0.293

AC:

1016

AN:

3470

East Asian (EAS)

AF:

0.00308

AC:

AN:

5192

South Asian (SAS)

AF:

0.109

AC:

526

AN:

4822

European-Finnish (FIN)

AF:

0.199

AC:

2098

AN:

10548

Middle Eastern (MID)

AF:

0.248

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.264

AC:

17962

AN:

67958

Other (OTH)

AF:

0.191

AC:

404

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1085

2169

3254

4338

5423

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

288

576

864

1152

1440

<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:

0.229

Hom.:

13739

Bravo

AF:

0.172

Asia WGS

AF:

0.0660

AC:

229

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.88

CADD

Benign

0.47

(source)

DANN

Benign

0.46

PhyloP100

-1.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

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

Computational scores

Splicing

Publications

Other links and lift over