chr17-18271367-G-A

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 11 publications found

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]

TOP3A Gene-Disease associations (from GenCC):

• microcephaly, growth restriction, and increased sister chromatid exchange 2

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P
• progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 5

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004618.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TOP3A	NM_004618.5	MANE Select	c.*3435C>T		downstream_gene	N/A	NP_004609.1	Q13472-1
	TOP3A	NM_001320759.2		c.*3435C>T		downstream_gene	N/A	NP_001307688.1	Q13472-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TOP3A	ENST00000321105.10	TSL:1 MANE Select	c.*3435C>T		downstream_gene	N/A	ENSP00000321636.5	Q13472-1
	TOP3A	ENST00000493648.1	TSL:2	n.*407C>T		downstream_gene	N/A	ENSP00000465014.1	K7EJ41

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

African (AFR) AC: 0 AN: 0

American (AMR) AF: 0.103 AC: 6 AN: 58

Ashkenazi Jewish (ASJ) AF: 0.333 AC: 2 AN: 6

East Asian (EAS) AF: 0.00 AC: 0 AN: 6

South Asian (SAS) AF: 0.146 AC: 29 AN: 198

European-Finnish (FIN) AF: 0.182 AC: 8 AN: 44

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4

European-Non Finnish (NFE) AF: 0.272 AC: 123 AN: 452

Other (OTH) AF: 0.158 AC: 6 AN: 38

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

African (AFR) AF: 0.346 AC: 14358 AN: 41452

American (AMR) AF: 0.248 AC: 3791 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.328 AC: 1138 AN: 3472

East Asian (EAS) AF: 0.0753 AC: 390 AN: 5182

South Asian (SAS) AF: 0.186 AC: 898 AN: 4818

European-Finnish (FIN) AF: 0.324 AC: 3423 AN: 10560

Middle Eastern (MID) AF: 0.296 AC: 87 AN: 294

European-Non Finnish (NFE) AF: 0.316 AC: 21455 AN: 67974

Other (OTH) AF: 0.289 AC: 609 AN: 2104

Alfa AF: 0.305 Hom.: 8801

Bravo AF: 0.297

Asia WGS AF: 0.152 AC: 531 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.6
DANN	Benign	0.62
PhyloP100		0.33

Splicing

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

Other links and lift over

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