3-25598337-T-A

Position:

chr3-25598337-T-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBS1BS2

The NM_001330700.2(TOP2B):c.4851A>T(p.Glu1617Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0254 in 1,609,852 control chromosomes in the GnomAD database, including 616 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.030 ( 85 hom., cov: 33)

Exomes 𝑓: 0.025 ( 531 hom. )

Consequence

TOP2B
NM_001330700.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.487

Variant links:

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 links:

TOP2B (HGNC:):

TOP2B links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), TOP2B. . Gene score misZ 3.8634 (greater than the threshold 3.09). Trascript score misZ 3.6879 (greater than threshold 3.09). GenCC has associacion of gene with B-cell immunodeficiency, distal limb anomalies, and urogenital malformations.

BP4

Computational evidence support a benign effect (MetaRNN=0.0016448498).

BP6

Variant 3-25598337-T-A is Benign according to our data. Variant chr3-25598337-T-A is described in ClinVar as [Benign]. Clinvar id is 1164865.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0303 (4619/152280) while in subpopulation AFR AF= 0.0464 (1929/41564). AF 95% confidence interval is 0.0447. There are 85 homozygotes in gnomad4. There are 2178 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 4619 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TOP2B	NM_001330700.2 linkuse as main transcript	c.4851A>T	p.Glu1617Asp	missense_variant	36/36	ENST00000264331.9	NP_001317629.1	Q02880-1
TOP2B	NM_001068.3 linkuse as main transcript	c.4836A>T	p.Glu1612Asp	missense_variant	36/36		NP_001059.2	Q02880-2Q59H80
TOP2B	XM_011534057.4 linkuse as main transcript	c.4740A>T	p.Glu1580Asp	missense_variant	35/35		XP_011532359.1
TOP2B	XM_047448821.1 linkuse as main transcript	c.4725A>T	p.Glu1575Asp	missense_variant	35/35		XP_047304777.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TOP2B	ENST00000264331.9 linkuse as main transcript	c.4851A>T	p.Glu1617Asp	missense_variant	36/36	5	NM_001330700.2	ENSP00000264331.4		Q02880-1

Frequencies

GnomAD3 genomes

AF:

0.0303

AC:

4618

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0465

Gnomad AMI

AF:

0.0154

Gnomad AMR

AF:

0.0325

Gnomad ASJ

AF:

0.0259

Gnomad EAS

AF:

0.000771

Gnomad SAS

AF:

0.0108

Gnomad FIN

AF:

0.0185

Gnomad MID

AF:

0.0443

Gnomad NFE

AF:

0.0257

Gnomad OTH

AF:

0.0354

GnomAD3 exomes

AF:

0.0217

AC:

5323

AN:

245794

Hom.:

AF XY:

0.0216

AC XY:

2877

AN XY:

133214

show subpopulations

Gnomad AFR exome

AF:

0.0472

Gnomad AMR exome

AF:

0.0158

Gnomad ASJ exome

AF:

0.0231

Gnomad EAS exome

AF:

0.000728

Gnomad SAS exome

AF:

0.0102

Gnomad FIN exome

AF:

0.0186

Gnomad NFE exome

AF:

0.0265

Gnomad OTH exome

AF:

0.0252

GnomAD4 exome

AF:

0.0249

AC:

36321

AN:

1457572

Hom.:

531

Cov.:

AF XY:

0.0245

AC XY:

17741

AN XY:

724702

show subpopulations

Gnomad4 AFR exome

AF:

0.0431

Gnomad4 AMR exome

AF:

0.0176

Gnomad4 ASJ exome

AF:

0.0243

Gnomad4 EAS exome

AF:

0.000479

Gnomad4 SAS exome

AF:

0.0105

Gnomad4 FIN exome

AF:

0.0202

Gnomad4 NFE exome

AF:

0.0268

Gnomad4 OTH exome

AF:

0.0260

GnomAD4 genome

AF:

0.0303

AC:

4619

AN:

152280

Hom.:

Cov.:

AF XY:

0.0292

AC XY:

2178

AN XY:

74466

show subpopulations

Gnomad4 AFR

AF:

0.0464

Gnomad4 AMR

AF:

0.0324

Gnomad4 ASJ

AF:

0.0259

Gnomad4 EAS

AF:

0.000772

Gnomad4 SAS

AF:

0.0108

Gnomad4 FIN

AF:

0.0185

Gnomad4 NFE

AF:

0.0257

Gnomad4 OTH

AF:

0.0355

Alfa

AF:

0.0227

Hom.:

Bravo

AF:

0.0327

TwinsUK

AF:

0.0229

AC:

ALSPAC

AF:

0.0288

AC:

111

ESP6500AA

AF:

0.0451

AC:

169

ESP6500EA

AF:

0.0259

AC:

212

ExAC

AF:

0.0230

AC:

2782

Asia WGS

AF:

0.00895

AC:

AN:

3478

EpiCase

AF:

0.0323

EpiControl

AF:

0.0290

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

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

AlphaMissense

Benign

0.062

BayesDel_addAF

Benign

-0.67

BayesDel_noAF

Benign

-0.70

CADD

Benign

0.0090

DANN

Benign

0.58

DEOGEN2

Benign

0.057

T;.

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.16

LIST_S2

Benign

0.52

T;T

MetaRNN

Benign

0.0016

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.65

N;.

PrimateAI

Uncertain

0.53

PROVEAN

Benign

0.79

N;N

REVEL

Benign

0.038

Sift

Benign

1.0

T;T

Sift4G

Benign

1.0

T;T

Polyphen

0.0

B;B

Vest4

0.081

MutPred

0.27

Gain of glycosylation at S1613 (P = 0.0068);.;

MPC

0.047

ClinPred

0.0014

GERP RS

-2.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.8

Varity_R

0.018

gMVP

0.055

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

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