17-18278230-TG-TGG

Variant names:

• chr17-18278230-T-TG
• rs752838075
• NM_004618.5:c.2271dupC

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_004618.5(TOP3A):​c.2271dupC​(p.Arg758GlnfsTer3) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000196 in 1,430,588 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000020 (0 hom.)
• Consequence: TOP3A NM_004618.5 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• 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]

ACMG classification

Verdict is Pathogenic. Variant got 14 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 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-18278230-T-TG is Pathogenic according to our data. Variant chr17-18278230-T-TG is described in ClinVar as [Pathogenic]. Clinvar id is 560203.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TOP3A	NM_004618.5	c.2271dupC	p.Arg758GlnfsTer3	frameshift_variant	Exon 18 of 19	ENST00000321105.10	NP_004609.1
TOP3A	NM_001320759.2	c.1986dupC	p.Arg663GlnfsTer3	frameshift_variant	Exon 17 of 18		NP_001307688.1
TOP3A	XM_047436633.1	c.1350dupC	p.Arg451GlnfsTer3	frameshift_variant	Exon 16 of 17		XP_047292589.1
TOP3A	XM_047436634.1	c.1350dupC	p.Arg451GlnfsTer3	frameshift_variant	Exon 16 of 17		XP_047292590.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TOP3A	ENST00000321105.10	c.2271dupC	p.Arg758GlnfsTer3	frameshift_variant	Exon 18 of 19	1	NM_004618.5	ENSP00000321636.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.0000196 AC: 28 AN: 1430588 Hom.: 0 Cov.: 32 AF XY: 0.0000226 AC XY: 16 AN XY: 707654

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000255

Gnomad4 SAS exome AF: 0.0000485

Gnomad4 FIN exome AF: 0.000229

Gnomad4 NFE exome AF: 0.00000914

Gnomad4 OTH exome AF: 0.0000170

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Jul 17, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 30057030) -

Jul 24, 2020

AiLife Diagnostics, AiLife Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Microcephaly, growth restriction, and increased sister chromatid exchange 2 Pathogenic:2

Aug 30, 2018

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Sep 01, 2022

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.005%). Frameshift variant is predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000560203 / PMID: 30057030). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

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

LitVar

Other links and lift over

dbSNP: rs752838075; hg19: chr17-18181544;