rs11540720

Variant names:

• chr17-40389572-C-A
• rs11540720
• NM_001067.4:c.4543G>T

Your query was ambiguous. Multiple possible variants found:

• chr17-40389572-C-A
• chr17-40389572-C-T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. 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. 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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.174
• Publications: 17 publications found

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

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001067.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TOP2A	NM_001067.4	MANE Select	c.4543G>T	p.Ala1515Ser	missense	Exon 35 of 35	NP_001058.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TOP2A	ENST00000423485.6	TSL:1 MANE Select	c.4543G>T	p.Ala1515Ser	missense	Exon 35 of 35	ENSP00000411532.1
	TOP2A	ENST00000917864.1		c.4360G>T	p.Ala1454Ser	missense	Exon 34 of 34	ENSP00000587923.1
	TOP2A	ENST00000917865.1		c.3928G>T	p.Ala1310Ser	missense	Exon 30 of 30	ENSP00000587924.1

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

GnomAD2 exomes AF: 0.0204 AC: 4715 AN: 230642 AF XY: 0.0189

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

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: 0 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

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

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: 33 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00663 AC: 32 AN: 4826

European-Finnish (FIN) AF: 0.0228 AC: 242 AN: 10610

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.0241 AC: 1636 AN: 68018

Other (OTH) AF: 0.0346 AC: 73 AN: 2110

Alfa AF: 0.0283 Hom.: 175

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 v4.9

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
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.69
FATHMM_MKL	Benign	0.085	N
LIST_S2	Benign	0.59	T
MetaRNN	Benign	0.0027	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L
PhyloP100		0.17
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.065
Sift	Benign	0.11	T
Sift4G	Benign	0.14	T
Polyphen		0.0	B
Vest4		0.015
MPC		0.13
ClinPred		0.014	T
GERP RS		2.2
PromoterAI		-0.011	Neutral
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)

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

Other links and lift over

dbSNP: rs11540720; hg19: chr17-38545824;