rs61739570

Variant names:

• chr3-25598337-T-A
• rs61739570
• NM_001330700.2:c.4851A>T

Your query was ambiguous. Multiple possible variants found:

• chr3-25598337-T-A
• chr3-25598337-T-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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. 14/21 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.487
• Publications: 10 publications found

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 Gene-Disease associations (from GenCC):

• B-cell immunodeficiency, distal limb anomalies, and urogenital malformations

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: ClinGen, Illumina, Ambry Genetics, PanelApp Australia
• neurodevelopmental disorder

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• 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 VariationId 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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 4619 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001330700.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TOP2B	NM_001330700.2	MANE Select	c.4851A>T	p.Glu1617Asp	missense	Exon 36 of 36	NP_001317629.1	Q02880-1
	TOP2B	NM_001068.3		c.4836A>T	p.Glu1612Asp	missense	Exon 36 of 36	NP_001059.2	Q59H80

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TOP2B	ENST00000264331.9	TSL:5 MANE Select	c.4851A>T	p.Glu1617Asp	missense	Exon 36 of 36	ENSP00000264331.4	Q02880-1
	TOP2B	ENST00000435706.7	TSL:1	c.4836A>T	p.Glu1612Asp	missense	Exon 36 of 36	ENSP00000396704.2
	TOP2B	ENST00000424225.2	TSL:1	c.4752A>T	p.Glu1584Asp	missense	Exon 36 of 36	ENSP00000391112.2

Frequencies

GnomAD3 genomes AF: 0.0303 AC: 4618 AN: 152162 Hom.: 85 Cov.: 33

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

GnomAD2 exomes AF: 0.0217 AC: 5323 AN: 245794 AF XY: 0.0216

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 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.: 30 AF XY: 0.0245 AC XY: 17741 AN XY: 724702

African (AFR) AF: 0.0431 AC: 1437 AN: 33316

American (AMR) AF: 0.0176 AC: 774 AN: 44064

Ashkenazi Jewish (ASJ) AF: 0.0243 AC: 632 AN: 26034

East Asian (EAS) AF: 0.000479 AC: 19 AN: 39642

South Asian (SAS) AF: 0.0105 AC: 898 AN: 85210

European-Finnish (FIN) AF: 0.0202 AC: 1075 AN: 53350

Middle Eastern (MID) AF: 0.0213 AC: 123 AN: 5762

European-Non Finnish (NFE) AF: 0.0268 AC: 29796 AN: 1109944

Other (OTH) AF: 0.0260 AC: 1567 AN: 60250

GnomAD4 genome AF: 0.0303 AC: 4619 AN: 152280 Hom.: 85 Cov.: 33 AF XY: 0.0292 AC XY: 2178 AN XY: 74466

African (AFR) AF: 0.0464 AC: 1929 AN: 41564

American (AMR) AF: 0.0324 AC: 496 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0259 AC: 90 AN: 3472

East Asian (EAS) AF: 0.000772 AC: 4 AN: 5178

South Asian (SAS) AF: 0.0108 AC: 52 AN: 4830

European-Finnish (FIN) AF: 0.0185 AC: 197 AN: 10620

Middle Eastern (MID) AF: 0.0442 AC: 13 AN: 294

European-Non Finnish (NFE) AF: 0.0257 AC: 1749 AN: 68006

Other (OTH) AF: 0.0355 AC: 75 AN: 2112

Alfa AF: 0.0227 Hom.: 37

Bravo AF: 0.0327

TwinsUK AF: 0.0229 AC: 85

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: 31 AN: 3478

EpiCase AF: 0.0323

EpiControl AF: 0.0290

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.67	T
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	N
LIST_S2	Benign	0.52	T
MetaRNN	Benign	0.0016	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.65	N
PhyloP100		-0.49
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	0.79	N
REVEL	Benign	0.038
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.081
MutPred		0.27		Gain of glycosylation at S1613 (P = 0.0068)
MPC		0.047
ClinPred		0.0014	T
GERP RS		-2.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Varity_R		0.018
gMVP		0.055
Mutation Taster		=95/5	polymorphism (auto)

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

Other links and lift over

dbSNP: rs61739570; hg19: chr3-25639828; COSMIC: COSV107262034;