rs12945597

Variant names:

• chr17-18271367-G-A
• rs12945597
• NM_004618.5:c.*3435C>T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004618.5(TOP3A):​c.*3435C>T variant causes a downstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.305 in 152,858 control chromosomes in the GnomAD database, including 7,440 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.31 (7413 hom., cov: 32)
  • Exomes 𝑓: 0.22 (27 hom.)
• Consequence: TOP3A NM_004618.5 downstream_gene
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.327

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.342 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TOP3A	NM_004618.5	c.*3435C>T		downstream_gene_variant		ENST00000321105.10	NP_004609.1
TOP3A	NM_001320759.2	c.*3435C>T		downstream_gene_variant			NP_001307688.1
TOP3A	XM_047436633.1	c.*3435C>T		downstream_gene_variant			XP_047292589.1
TOP3A	XM_047436634.1	c.*3435C>T		downstream_gene_variant			XP_047292590.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TOP3A	ENST00000321105.10	c.*3435C>T		downstream_gene_variant		1	NM_004618.5	ENSP00000321636.5
TOP3A	ENST00000493648.1	n.*407C>T		downstream_gene_variant		2		ENSP00000465014.1

Frequencies

GnomAD3 genomes AF: 0.305 AC: 46402 AN: 151934 Hom.: 7412 Cov.: 32

Gnomad AFR AF: 0.346

Gnomad AMI AF: 0.319

Gnomad AMR AF: 0.248

Gnomad ASJ AF: 0.328

Gnomad EAS AF: 0.0747

Gnomad SAS AF: 0.185

Gnomad FIN AF: 0.324

Gnomad MID AF: 0.304

Gnomad NFE AF: 0.316

Gnomad OTH AF: 0.293

GnomAD4 exome AF: 0.216 AC: 174 AN: 806 Hom.: 27 AF XY: 0.187 AC XY: 85 AN XY: 454

Gnomad4 AMR exome AF: 0.103

Gnomad4 ASJ exome AF: 0.333

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.146

Gnomad4 FIN exome AF: 0.182

Gnomad4 NFE exome AF: 0.272

Gnomad4 OTH exome AF: 0.158

GnomAD4 genome AF: 0.305 AC: 46439 AN: 152052 Hom.: 7413 Cov.: 32 AF XY: 0.301 AC XY: 22364 AN XY: 74324

Gnomad4 AFR AF: 0.346

Gnomad4 AMR AF: 0.248

Gnomad4 ASJ AF: 0.328

Gnomad4 EAS AF: 0.0753

Gnomad4 SAS AF: 0.186

Gnomad4 FIN AF: 0.324

Gnomad4 NFE AF: 0.316

Gnomad4 OTH AF: 0.289

Alfa AF: 0.304 Hom.: 6632

Bravo AF: 0.297

Asia WGS AF: 0.152 AC: 531 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.6
DANN	Benign	0.62

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs12945597; hg19: chr17-18174681; COSMIC: COSV58175902;