chr3-25598346-A-T

Position:

• chr3-25598346-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_001330700.2(TOP2B):​c.4842T>A​(p.Asp1614Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: TOP2B NM_001330700.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.34

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TOP2B	NM_001330700.2	c.4842T>A	p.Asp1614Glu	missense_variant	36/36	ENST00000264331.9	NP_001317629.1
TOP2B	NM_001068.3	c.4827T>A	p.Asp1609Glu	missense_variant	36/36		NP_001059.2
TOP2B	XM_011534057.4	c.4731T>A	p.Asp1577Glu	missense_variant	35/35		XP_011532359.1
TOP2B	XM_047448821.1	c.4716T>A	p.Asp1572Glu	missense_variant	35/35		XP_047304777.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TOP2B	ENST00000264331.9	c.4842T>A	p.Asp1614Glu	missense_variant	36/36	5	NM_001330700.2	ENSP00000264331.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Mar 23, 2023

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; De novo variant with confirmed parentage in a patient referred for genetic testing at GeneDx; however, the reported clinical features are only partially consistent with the features typically observed in individuals with pathogenic variants in this gene; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Uncertain	0.047	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.19	T;.
Eigen	Benign	0.14
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.79	T;T
M_CAP	Benign	0.026	D
MetaRNN	Uncertain	0.45	T;T
MetaSVM	Benign	-0.64	T
MutationAssessor	Benign	2.0	M;.
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-1.9	N;N
REVEL	Uncertain	0.29
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.012	D;D
Polyphen		0.99	D;D
Vest4		0.51
MutPred		0.31		Gain of glycosylation at Y1609 (P = 0.004);.;
MVP		0.55
MPC		0.33
ClinPred		0.86	D
GERP RS		2.1
Varity_R		0.35
gMVP		0.17

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: rs111812268; hg19: chr3-25639837;