17-40406827-C-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_001067.4(TOP2A):c.1737+5G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00483 in 1,595,584 control chromosomes in the GnomAD database, including 30 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0036 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0050 ( 29 hom. )

Consequence

TOP2A
NM_001067.4 splice_region, intron

Scores

Splicing: ADA: 0.1813

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3

Conservation

PhyloP100: -0.434

Variant links:

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]

TOP2A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.87).

BP6

Variant 17-40406827-C-T is Benign according to our data. Variant chr17-40406827-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 587549.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.

BS2

High AC in GnomAd4 at 555 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
TOP2A	NM_001067.4 link	c.1737+5G>A	splice_region_variant, intron_variant	Intron 14 of 34	ENST00000423485.6	NP_001058.2	P11388-1
TOP2A	XM_005257632.2 link	c.1701+5G>A	splice_region_variant, intron_variant	Intron 14 of 34		XP_005257689.1
TOP2A	XM_011525165.3 link	c.1737+5G>A	splice_region_variant, intron_variant	Intron 14 of 31		XP_011523467.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TOP2A	ENST00000423485.6 link	c.1737+5G>A		splice_region_variant, intron_variant	Intron 14 of 34	1	NM_001067.4	ENSP00000411532.1		P11388-1

Frequencies

GnomAD3 genomes

AF:

0.00364

AC:

554

AN:

152100

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000918

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00354

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.000384

Gnomad SAS

AF:

0.00394

Gnomad FIN

AF:

0.00358

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00582

Gnomad OTH

AF:

0.00239

GnomAD3 exomes

AF:

0.00409

AC:

945

AN:

230946

Hom.:

AF XY:

0.00441

AC XY:

552

AN XY:

125046

show subpopulations

Gnomad AFR exome

AF:

0.000835

Gnomad AMR exome

AF:

0.00202

Gnomad ASJ exome

AF:

0.000934

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00424

Gnomad FIN exome

AF:

0.00332

Gnomad NFE exome

AF:

0.00614

Gnomad OTH exome

AF:

0.00628

GnomAD4 exome

AF:

0.00496

AC:

7153

AN:

1443366

Hom.:

Cov.:

AF XY:

0.00508

AC XY:

3644

AN XY:

717686

show subpopulations

Gnomad4 AFR exome

AF:

0.000602

Gnomad4 AMR exome

AF:

0.00179

Gnomad4 ASJ exome

AF:

0.000697

Gnomad4 EAS exome

AF:

0.0000253

Gnomad4 SAS exome

AF:

0.00436

Gnomad4 FIN exome

AF:

0.00402

Gnomad4 NFE exome

AF:

0.00563

Gnomad4 OTH exome

AF:

0.00403

GnomAD4 genome

AF:

0.00365

AC:

555

AN:

152218

Hom.:

Cov.:

AF XY:

0.00356

AC XY:

265

AN XY:

74432

show subpopulations

Gnomad4 AFR

AF:

0.000915

Gnomad4 AMR

AF:

0.00354

Gnomad4 ASJ

AF:

0.000576

Gnomad4 EAS

AF:

0.000385

Gnomad4 SAS

AF:

0.00415

Gnomad4 FIN

AF:

0.00358

Gnomad4 NFE

AF:

0.00582

Gnomad4 OTH

AF:

0.00236

Alfa

AF:

0.00479

Hom.:

Bravo

AF:

0.00322

Asia WGS

AF:

0.00231

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

TOP2A: BP4, BS2 -

Aug 07, 2018

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

TOP2A-related disorder

Benign:1

Feb 11, 2020

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely 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

-0.87

CADD

Benign

0.49

DANN

Benign

0.49

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.18

dbscSNV1_RF

Benign

0.16

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over