dbSNP rs796052143: TOP2A:p.Ile88Thr (chr17-40416427-A-G) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM2PP3_ModerateBP6

The NM_001067.4(TOP2A):c.263T>C(p.Ile88Thr) 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 Likely benign (no stars).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

TOP2A
NM_001067.4 missense

Scores

Clinical Significance

Likely benign no assertion criteria provided B:1

Conservation

PhyloP100: 8.78

Publications

1 publications found

Variant links:

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]

TOP2A links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.901

BP6

Variant 17-40416427-A-G is Benign according to our data. Variant chr17-40416427-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 207835.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001067.4. 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
	TOP2A	NM_001067.4	MANE Select	c.263T>C	p.Ile88Thr	missense	Exon 3 of 35	NP_001058.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TOP2A	ENST00000423485.6	TSL:1 MANE Select	c.263T>C	p.Ile88Thr	missense	Exon 3 of 35	ENSP00000411532.1	P11388-1
TOP2A	ENST00000917864.1		c.263T>C	p.Ile88Thr	missense	Exon 3 of 34	ENSP00000587923.1
TOP2A	ENST00000917865.1		c.263T>C	p.Ile88Thr	missense	Exon 3 of 30	ENSP00000587924.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1425380

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

707976

African (AFR)

AF:

0.00

AC:

AN:

32656

American (AMR)

AF:

0.00

AC:

AN:

41196

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25568

East Asian (EAS)

AF:

0.00

AC:

AN:

38962

South Asian (SAS)

AF:

0.00

AC:

AN:

82366

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52268

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5700

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1087528

Other (OTH)

AF:

0.00

AC:

AN:

59136

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

Long QT syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.36

BayesDel_noAF

Pathogenic

0.28

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.55

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.88

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Pathogenic

1.0

M_CAP

Uncertain

0.12

MetaRNN

Pathogenic

0.90

MetaSVM

Uncertain

0.39

MutationAssessor

Pathogenic

4.3

PhyloP100

8.8

PrimateAI

Pathogenic

0.91

PROVEAN

Pathogenic

-4.7

REVEL

Pathogenic

0.75

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.95

MutPred

0.75

Loss of stability (P = 0.0055)

MVP

0.81

MPC

2.2

ClinPred

1.0

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.88

gMVP

0.87

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over