17-18274827-C-CG

Position:

• chr17-18274827-C-CG

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PM4

The NM_004618.5(TOP3A):​c.2980_2981insC​(p.Arg994ProfsTer13) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: TOP3A NM_004618.5 frameshift
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.37

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Frameshift in the end of transcript resulting in stoplost. Downstream stopcodon found after 1008 codons.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TOP3A	NM_004618.5	c.2980_2981insC	p.Arg994ProfsTer13	frameshift_variant	19/19	ENST00000321105.10	NP_004609.1
TOP3A	NM_001320759.2	c.2695_2696insC	p.Arg899ProfsTer13	frameshift_variant	18/18		NP_001307688.1
TOP3A	XM_047436633.1	c.2059_2060insC	p.Arg687ProfsTer13	frameshift_variant	17/17		XP_047292589.1
TOP3A	XM_047436634.1	c.2059_2060insC	p.Arg687ProfsTer13	frameshift_variant	17/17		XP_047292590.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TOP3A	ENST00000321105.10	c.2980_2981insC	p.Arg994ProfsTer13	frameshift_variant	19/19	1	NM_004618.5	ENSP00000321636	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

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

Labcorp Genetics (formerly Invitae), Labcorp

Aug 19, 2022

Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant has not been reported in the literature in individuals affected with TOP3A-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change results in a frameshift in the TOP3A gene (p.Arg994Profs*13). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 8 amino acid(s) of the TOP3A protein and extend the protein by 4 additional amino acid residues. -

Computational scores

Source: dbNSFP v4.3

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-18178141;