17-40400518-T-C

Variant names:

• chr17-40400518-T-C
• rs471692
• NM_001067.4:c.2799+11A>G

Variant summary

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

The NM_001067.4(TOP2A):​c.2799+11A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.811 in 1,601,858 control chromosomes in the GnomAD database, including 529,112 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 0.85 (55111 hom., cov: 30)
  • Exomes 𝑓: 0.81 (474001 hom.)
• Consequence: TOP2A NM_001067.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.20
• Publications: 18 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 (BayesDel_noAF=-0.86).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.951 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TOP2A	NM_001067.4	c.2799+11A>G		intron_variant	Intron 22 of 34	ENST00000423485.6	NP_001058.2
TOP2A	XM_005257632.2	c.2763+11A>G		intron_variant	Intron 22 of 34		XP_005257689.1
TOP2A	XM_011525165.3	c.2799+11A>G		intron_variant	Intron 22 of 31		XP_011523467.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TOP2A	ENST00000423485.6	c.2799+11A>G		intron_variant	Intron 22 of 34	1	NM_001067.4	ENSP00000411532.1

Frequencies

GnomAD3 genomes AF: 0.847 AC: 128717 AN: 152042 Hom.: 55047 Cov.: 30

Gnomad AFR AF: 0.959

Gnomad AMI AF: 0.828

Gnomad AMR AF: 0.735

Gnomad ASJ AF: 0.840

Gnomad EAS AF: 0.750

Gnomad SAS AF: 0.691

Gnomad FIN AF: 0.866

Gnomad MID AF: 0.905

Gnomad NFE AF: 0.819

Gnomad OTH AF: 0.839

GnomAD2 exomes AF: 0.788 AC: 186520 AN: 236714 AF XY: 0.787

Gnomad AFR exome AF: 0.960

Gnomad AMR exome AF: 0.633

Gnomad ASJ exome AF: 0.838

Gnomad EAS exome AF: 0.734

Gnomad FIN exome AF: 0.862

Gnomad NFE exome AF: 0.819

Gnomad OTH exome AF: 0.808

GnomAD4 exome AF: 0.807 AC: 1169788 AN: 1449698 Hom.: 474001 Cov.: 46 AF XY: 0.804 AC XY: 579557 AN XY: 720710

African (AFR) AF: 0.965 AC: 31679 AN: 32830

American (AMR) AF: 0.645 AC: 26770 AN: 41484

Ashkenazi Jewish (ASJ) AF: 0.841 AC: 21552 AN: 25626

East Asian (EAS) AF: 0.737 AC: 29201 AN: 39608

South Asian (SAS) AF: 0.706 AC: 59096 AN: 83734

European-Finnish (FIN) AF: 0.857 AC: 45511 AN: 53110

Middle Eastern (MID) AF: 0.863 AC: 4931 AN: 5712

European-Non Finnish (NFE) AF: 0.814 AC: 901952 AN: 1107726

Other (OTH) AF: 0.820 AC: 49096 AN: 59868

GnomAD4 genome AF: 0.847 AC: 128837 AN: 152160 Hom.: 55111 Cov.: 30 AF XY: 0.843 AC XY: 62703 AN XY: 74392

African (AFR) AF: 0.959 AC: 39834 AN: 41548

American (AMR) AF: 0.735 AC: 11225 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.840 AC: 2913 AN: 3468

East Asian (EAS) AF: 0.749 AC: 3872 AN: 5168

South Asian (SAS) AF: 0.691 AC: 3329 AN: 4818

European-Finnish (FIN) AF: 0.866 AC: 9166 AN: 10584

Middle Eastern (MID) AF: 0.915 AC: 269 AN: 294

European-Non Finnish (NFE) AF: 0.819 AC: 55706 AN: 67996

Other (OTH) AF: 0.841 AC: 1771 AN: 2106

Alfa AF: 0.848 Hom.: 11845

Bravo AF: 0.841

Asia WGS AF: 0.780 AC: 2711 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	1.3
DANN	Benign	0.52
PhyloP100		-1.2
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs471692; hg19: chr17-38556770;