17-40392315-C-A
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Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2
The NM_001067.4(TOP2A):c.3991G>T(p.Asp1331Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000532 in 1,597,496 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000055 ( 0 hom. )
Consequence
TOP2A
NM_001067.4 missense
NM_001067.4 missense
Scores
11
8
Clinical Significance
Conservation
PhyloP100: 1.76
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -4 ACMG points.
BS2
High AC in GnomAd4 at 5 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TOP2A | NM_001067.4 | c.3991G>T | p.Asp1331Tyr | missense_variant | 31/35 | ENST00000423485.6 | |
TOP2A | XM_005257632.2 | c.3955G>T | p.Asp1319Tyr | missense_variant | 31/35 | ||
TOP2A | XM_011525165.3 | c.3991G>T | p.Asp1331Tyr | missense_variant | 31/32 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TOP2A | ENST00000423485.6 | c.3991G>T | p.Asp1331Tyr | missense_variant | 31/35 | 1 | NM_001067.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000329 AC: 5AN: 152090Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000228 AC: 5AN: 219334Hom.: 0 AF XY: 0.0000169 AC XY: 2AN XY: 118518
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GnomAD4 exome AF: 0.0000553 AC: 80AN: 1445406Hom.: 0 Cov.: 32 AF XY: 0.0000543 AC XY: 39AN XY: 717636
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GnomAD4 genome AF: 0.0000329 AC: 5AN: 152090Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74272
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 30, 2023 | The c.3991G>T (p.D1331Y) alteration is located in exon 31 (coding exon 31) of the TOP2A gene. This alteration results from a G to T substitution at nucleotide position 3991, causing the aspartic acid (D) at amino acid position 1331 to be replaced by a tyrosine (Y). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Benign
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Benign
T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T
M_CAP
Benign
T
MetaRNN
Uncertain
D
MetaSVM
Benign
T
MutationAssessor
Uncertain
M
MutationTaster
Benign
D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D
REVEL
Benign
Sift
Uncertain
D
Sift4G
Uncertain
D
Polyphen
D
Vest4
MutPred
Gain of phosphorylation at D1331 (P = 0.0037);
MVP
MPC
ClinPred
D
GERP RS
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gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_AG_spliceai
Position offset: -7
Find out detailed SpliceAI scores and Pangolin per-transcript scores at