rs267607133

Positions:

• chr17-40408007-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP3 BP6

The ENST00000423485.6(TOP2A):​c.1460G>A​(p.Arg487Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as protective (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TOP2A ENST00000423485.6 missense
• Clinical Significance: protective no assertion criteria provided B:1
• Conservation: PhyloP100: 7.89

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.755
• BP6: Variant 17-40408007-C-T is Benign according to our data. Variant chr17-40408007-C-T is described in ClinVar as [protective]. Clinvar id is 16772.Status of the report is no_assertion_criteria_provided, 0 stars. We mark this variant Likely_benign, oryginal submission is: [protective].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TOP2A	NM_001067.4	c.1460G>A	p.Arg487Lys	missense_variant	12/35	ENST00000423485.6	NP_001058.2
TOP2A	XM_005257632.2	c.1424G>A	p.Arg475Lys	missense_variant	12/35		XP_005257689.1
TOP2A	XM_011525165.3	c.1460G>A	p.Arg487Lys	missense_variant	12/32		XP_011523467.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TOP2A	ENST00000423485.6	c.1460G>A	p.Arg487Lys	missense_variant	12/35	1	NM_001067.4	ENSP00000411532	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: protective

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

Dna topoisomerase II, resistance to inhibition of, by amsacrine Benign:1

protective, no assertion criteria provided

literature only

OMIM

Sep 01, 1991

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.45
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.18	T
Eigen	Benign	0.033
Eigen_PC	Benign	0.20
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.012	T
MetaRNN	Pathogenic	0.75	D
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-1.9	N
REVEL	Uncertain	0.29
Sift	Benign	0.043	D
Sift4G	Benign	0.13	T
Polyphen		0.021	B
Vest4		0.89
MutPred		0.79		Loss of methylation at R487 (P = 0.0354);
MVP		0.85
MPC		1.0
ClinPred		0.94	D
GERP RS		4.5
Varity_R		0.63
gMVP		0.96

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: rs267607133; hg19: chr17-38564259;