chr3-25598358-A-G

Position:

• chr3-25598358-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001330700.2(TOP2B):​c.4830T>C​(p.Phe1610Phe) variant causes a synonymous change. The variant allele was found at a frequency of 0.0381 in 1,613,290 control chromosomes in the GnomAD database, including 1,556 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.032 (148 hom., cov: 33)
  • Exomes 𝑓: 0.039 (1408 hom.)
• Consequence: TOP2B NM_001330700.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 4.65

Genes affected

TOP2B (HGNC:11990): (DNA topoisomerase II beta) 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, beta, is localized to chromosome 3 and the alpha form is localized to chromosome 17. 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. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2016]

TOP2B (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 3-25598358-A-G is Benign according to our data. Variant chr3-25598358-A-G is described in ClinVar as [Benign]. Clinvar id is 1164142.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0514 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TOP2B	NM_001330700.2	c.4830T>C	p.Phe1610Phe	synonymous_variant	36/36	ENST00000264331.9	NP_001317629.1
TOP2B	NM_001068.3	c.4815T>C	p.Phe1605Phe	synonymous_variant	36/36		NP_001059.2
TOP2B	XM_011534057.4	c.4719T>C	p.Phe1573Phe	synonymous_variant	35/35		XP_011532359.1
TOP2B	XM_047448821.1	c.4704T>C	p.Phe1568Phe	synonymous_variant	35/35		XP_047304777.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TOP2B	ENST00000264331.9	c.4830T>C	p.Phe1610Phe	synonymous_variant	36/36	5	NM_001330700.2	ENSP00000264331.4

Frequencies

GnomAD3 genomes AF: 0.0323 AC: 4914 AN: 152212 Hom.: 148 Cov.: 33

Gnomad AFR AF: 0.00697

Gnomad AMI AF: 0.00330

Gnomad AMR AF: 0.0240

Gnomad ASJ AF: 0.0159

Gnomad EAS AF: 0.000384

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.0519

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0529

Gnomad OTH AF: 0.0229

GnomAD3 exomes AF: 0.0289 AC: 7177 AN: 248558 Hom.: 159 AF XY: 0.0284 AC XY: 3834 AN XY: 134888

Gnomad AFR exome AF: 0.00576

Gnomad AMR exome AF: 0.0119

Gnomad ASJ exome AF: 0.0172

Gnomad EAS exome AF: 0.0000557

Gnomad SAS exome AF: 0.000492

Gnomad FIN exome AF: 0.0494

Gnomad NFE exome AF: 0.0464

Gnomad OTH exome AF: 0.0317

GnomAD4 exome AF: 0.0387 AC: 56593 AN: 1460960 Hom.: 1408 Cov.: 30 AF XY: 0.0376 AC XY: 27298 AN XY: 726736

Gnomad4 AFR exome AF: 0.00523

Gnomad4 AMR exome AF: 0.0133

Gnomad4 ASJ exome AF: 0.0158

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000650

Gnomad4 FIN exome AF: 0.0513

Gnomad4 NFE exome AF: 0.0456

Gnomad4 OTH exome AF: 0.0313

GnomAD4 genome AF: 0.0323 AC: 4913 AN: 152330 Hom.: 148 Cov.: 33 AF XY: 0.0316 AC XY: 2354 AN XY: 74500

Gnomad4 AFR AF: 0.00695

Gnomad4 AMR AF: 0.0239

Gnomad4 ASJ AF: 0.0159

Gnomad4 EAS AF: 0.000385

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.0519

Gnomad4 NFE AF: 0.0529

Gnomad4 OTH AF: 0.0227

Alfa AF: 0.0428 Hom.: 111

Bravo AF: 0.0268

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.0417

EpiControl AF: 0.0396

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	7.2
DANN	Benign	0.86
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs11548723; hg19: chr3-25639849;