rs11540720

chr17-40389572-C-Achr17-40389572-C-T

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 1P and 12B. PP2 BP4_Strong BA1

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. 14/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.037 (171 hom., cov: 32)
  • Exomes 𝑓: 0.024 (492 hom.)
• Consequence: TOP2A NM_001067.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.174

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]

ACMG classification

Verdict is Benign. Variant got -11 ACMG points.

• PP2: Missense variant where missense usually causes diseases, TOP2A
• 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/exons	MANE	UniProt
TOP2A	NM_001067.4	c.4543G>T	p.Ala1515Ser	missense_variant	35/35	ENST00000423485.6
TOP2A	XM_005257632.2	c.4507G>T	p.Ala1503Ser	missense_variant	35/35

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TOP2A	ENST00000423485.6	c.4543G>T	p.Ala1515Ser	missense_variant	35/35	1	NM_001067.4	P1
TOP2A	ENST00000577541.1	c.31G>T	p.Ala11Ser	missense_variant	1/2	2
TOP2A	ENST00000578412.1	n.872G>T		non_coding_transcript_exon_variant	3/3	2

Frequencies

GnomAD3 genomes AF: 0.0370 AC: 5631 AN: 152078 Hom.: 167 Cov.: 32

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

GnomAD3 exomes AF: 0.0204 AC: 4715 AN: 230642 Hom.: 73 AF XY: 0.0189 AC XY: 2350 AN XY: 124662

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 SAS exome AF: 0.00646

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.: 31 AF XY: 0.0230 AC XY: 16553 AN XY: 720228

Gnomad4 AFR exome AF: 0.0767

Gnomad4 AMR exome AF: 0.0148

Gnomad4 ASJ exome AF: 0.0113

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00695

Gnomad4 FIN exome AF: 0.0219

Gnomad4 NFE exome AF: 0.0246

Gnomad4 OTH exome AF: 0.0268

GnomAD4 genome AF: 0.0372 AC: 5656 AN: 152196 Hom.: 171 Cov.: 32 AF XY: 0.0361 AC XY: 2687 AN XY: 74412

Gnomad4 AFR AF: 0.0766

Gnomad4 AMR AF: 0.0295

Gnomad4 ASJ AF: 0.00952

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00663

Gnomad4 FIN AF: 0.0228

Gnomad4 NFE AF: 0.0241

Gnomad4 OTH AF: 0.0346

Alfa AF: 0.0291 Hom.: 73

Bravo AF: 0.0391

TwinsUK AF: 0.0264 AC: 98

ALSPAC AF: 0.0257 AC: 99

ESP6500AA AF: 0.0800 AC: 296

ESP6500EA AF: 0.0221 AC: 181

ExAC AF: 0.0197 AC: 2376

Asia WGS AF: 0.0120 AC: 40 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	T
BayesDel_noAF	Benign	-0.59
Cadd	Benign	12
Dann	Benign	0.97
DEOGEN2	Benign	0.053	T;T
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.69
FATHMM_MKL	Benign	0.085	N
LIST_S2	Benign	0.59	T;T
MetaRNN	Benign	0.0027	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L;.
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.29	T
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	T
GERP RS		2.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.052
gMVP		0.088

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

Other links and lift over

dbSNP: rs11540720; hg19: chr17-38545824;