rs752838075
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Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_StrongPM2
The ENST00000321105.10(TOP3A):c.2271del(p.Arg758GlyfsTer15) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000821 in 1,582,720 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000084 ( 0 hom. )
Consequence
TOP3A
ENST00000321105.10 frameshift
ENST00000321105.10 frameshift
Scores
Not classified
Clinical Significance
Not reported in ClinVar
Conservation
PhyloP100: 0.342
Genes affected
TOP3A (HGNC:11992): (DNA topoisomerase III alpha) This gene encodes a DNA topoisomerase, an enzyme that controls and alters the topologic states of DNA during transcription. This enzyme catalyzes the transient breaking and rejoining of a single strand of DNA which allows the strands to pass through one another, thus reducing the number of supercoils and altering the topology of DNA. This enzyme forms a complex with BLM which functions in the regulation of recombination in somatic cells. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Mar 2016]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.245 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| TOP3A | NM_004618.5 | c.2271del | p.Arg758GlyfsTer15 | frameshift_variant | 18/19 | ENST00000321105.10 | NP_004609.1 | |
| TOP3A | NM_001320759.2 | c.1986del | p.Arg663GlyfsTer15 | frameshift_variant | 17/18 | NP_001307688.1 | ||
| TOP3A | XM_047436633.1 | c.1350del | p.Arg451GlyfsTer15 | frameshift_variant | 16/17 | XP_047292589.1 | ||
| TOP3A | XM_047436634.1 | c.1350del | p.Arg451GlyfsTer15 | frameshift_variant | 16/17 | XP_047292590.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| TOP3A | ENST00000321105.10 | c.2271del | p.Arg758GlyfsTer15 | frameshift_variant | 18/19 | 1 | NM_004618.5 | ENSP00000321636 | P1 |
Frequencies
GnomAD3 genomes 0.00000657 AC: 1AN: 152108Hom.: 0 Cov.: 33
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GnomAD4 exome AF: 0.00000839 AC: 12AN: 1430612Hom.: 0 Cov.: 32 AF XY: 0.0000113 AC XY: 8AN XY: 707662
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GnomAD4 genome 0.00000657 AC: 1AN: 152108Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74294
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at