rs13695

Variant names:

• chr17-40388941-C-T
• rs13695
• NM_001067.4:c.*578G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.77

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 (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	c.*578G>A		3_prime_UTR_variant	Exon 35 of 35	ENST00000423485.6	NP_001058.2
TOP2A	XM_005257632.2	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	c.*578G>A		3_prime_UTR_variant	Exon 35 of 35	1	NM_001067.4	ENSP00000411532.1
TOP2A	ENST00000577541.1	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.: 32

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.: 0 AF XY: 0.201 AC XY: 5192 AN XY: 25780

Gnomad4 AFR exome AF: 0.0640 AC: 162 AN: 2532

Gnomad4 AMR exome AF: 0.146 AC: 237 AN: 1628

Gnomad4 ASJ exome AF: 0.270 AC: 965 AN: 3578

Gnomad4 EAS exome AF: 0.000236 AC: 2 AN: 8486

Gnomad4 SAS exome AF: 0.0796 AC: 39 AN: 490

Gnomad4 FIN exome AF: 0.210 AC: 101 AN: 480

Gnomad4 NFE exome AF: 0.255 AC: 8604 AN: 33696

Gnomad4 Remaining exome AF: 0.217 AC: 1002 AN: 4614

GnomAD4 genome AF: 0.179 AC: 27270 AN: 152064 Hom.: 3183 Cov.: 32 AF XY: 0.173 AC XY: 12873 AN XY: 74346

Gnomad4 AFR AF: 0.0646 AC: 0.0646296 AN: 0.0646296

Gnomad4 AMR AF: 0.152 AC: 0.152359 AN: 0.152359

Gnomad4 ASJ AF: 0.293 AC: 0.292795 AN: 0.292795

Gnomad4 EAS AF: 0.00308 AC: 0.00308166 AN: 0.00308166

Gnomad4 SAS AF: 0.109 AC: 0.109083 AN: 0.109083

Gnomad4 FIN AF: 0.199 AC: 0.1989 AN: 0.1989

Gnomad4 NFE AF: 0.264 AC: 0.26431 AN: 0.26431

Gnomad4 OTH AF: 0.191 AC: 0.191469 AN: 0.191469

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
DANN	Benign	0.46
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	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

Publications

LitVar

Other links and lift over

dbSNP: rs13695; hg19: chr17-38545193;