17-40390022-A-C

Variant names:

• chr17-40390022-A-C
• rs17680289
• NM_001067.4:c.4410T>G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_001067.4(TOP2A):​c.4410T>G​(p.Thr1470Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0185 in 1,613,910 control chromosomes in the GnomAD database, including 376 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.012 (21 hom., cov: 32)
  • Exomes 𝑓: 0.019 (355 hom.)
• Consequence: TOP2A NM_001067.4 synonymous
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: -0.421

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 17-40390022-A-C is Benign according to our data. Variant chr17-40390022-A-C is described in ClinVar as [Benign]. Clinvar id is 3058908.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP7: Synonymous conserved (PhyloP=-0.421 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0123 (1880/152300) while in subpopulation NFE AF= 0.0204 (1388/68036). AF 95% confidence interval is 0.0195. There are 21 homozygotes in gnomad4. There are 886 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1880 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TOP2A	NM_001067.4	c.4410T>G	p.Thr1470Thr	synonymous_variant	Exon 34 of 35	ENST00000423485.6	NP_001058.2
TOP2A	XM_005257632.2	c.4374T>G	p.Thr1458Thr	synonymous_variant	Exon 34 of 35		XP_005257689.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TOP2A	ENST00000423485.6	c.4410T>G	p.Thr1470Thr	synonymous_variant	Exon 34 of 35	1	NM_001067.4	ENSP00000411532.1
TOP2A	ENST00000578412.1	n.739T>G		non_coding_transcript_exon_variant	Exon 2 of 3	2

Frequencies

GnomAD3 genomes AF: 0.0124 AC: 1881 AN: 152182 Hom.: 21 Cov.: 32

Gnomad AFR AF: 0.00408

Gnomad AMI AF: 0.0154

Gnomad AMR AF: 0.0125

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00352

Gnomad FIN AF: 0.00697

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0204

Gnomad OTH AF: 0.00956

GnomAD3 exomes AF: 0.0116 AC: 2896 AN: 248988 Hom.: 25 AF XY: 0.0119 AC XY: 1609 AN XY: 135116

Gnomad AFR exome AF: 0.00459

Gnomad AMR exome AF: 0.00780

Gnomad ASJ exome AF: 0.00179

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00481

Gnomad FIN exome AF: 0.00845

Gnomad NFE exome AF: 0.0189

Gnomad OTH exome AF: 0.0126

GnomAD4 exome AF: 0.0192 AC: 28039 AN: 1461610 Hom.: 355 Cov.: 31 AF XY: 0.0184 AC XY: 13402 AN XY: 727080

Gnomad4 AFR exome AF: 0.00323

Gnomad4 AMR exome AF: 0.00785

Gnomad4 ASJ exome AF: 0.00245

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00508

Gnomad4 FIN exome AF: 0.00940

Gnomad4 NFE exome AF: 0.0230

Gnomad4 OTH exome AF: 0.0168

GnomAD4 genome AF: 0.0123 AC: 1880 AN: 152300 Hom.: 21 Cov.: 32 AF XY: 0.0119 AC XY: 886 AN XY: 74474

Gnomad4 AFR AF: 0.00407

Gnomad4 AMR AF: 0.0125

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00332

Gnomad4 FIN AF: 0.00697

Gnomad4 NFE AF: 0.0204

Gnomad4 OTH AF: 0.00946

Alfa AF: 0.0177 Hom.: 36

Bravo AF: 0.0123

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.0196

EpiControl AF: 0.0179

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

TOP2A-related disorder Benign:1

May 30, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	7.0
DANN	Benign	0.76

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs17680289; hg19: chr17-38546274;