17-18277682-G-A

Position:

• chr17-18277682-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_004618.5(TOP3A):​c.2820C>T​(p.Thr940=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00122 in 1,605,208 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0022 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0011 (4 hom.)
• Consequence: TOP3A NM_004618.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.0270

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BP6: Variant 17-18277682-G-A is Benign according to our data. Variant chr17-18277682-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 916326.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.027 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00222 (338/152364) while in subpopulation AFR AF= 0.00354 (147/41582). AF 95% confidence interval is 0.00307. There are 0 homozygotes in gnomad4. There are 166 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TOP3A	NM_004618.5	c.2820C>T	p.Thr940=	synonymous_variant	18/19	ENST00000321105.10	NP_004609.1
TOP3A	NM_001320759.2	c.2535C>T	p.Thr845=	synonymous_variant	17/18		NP_001307688.1
TOP3A	XM_047436633.1	c.1899C>T	p.Thr633=	synonymous_variant	16/17		XP_047292589.1
TOP3A	XM_047436634.1	c.1899C>T	p.Thr633=	synonymous_variant	16/17		XP_047292590.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TOP3A	ENST00000321105.10	c.2820C>T	p.Thr940=	synonymous_variant	18/19	1	NM_004618.5	ENSP00000321636	P1

Frequencies

GnomAD3 genomes AF: 0.00223 AC: 339 AN: 152246 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00357

Gnomad AMI AF: 0.0186

Gnomad AMR AF: 0.00183

Gnomad ASJ AF: 0.00662

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000659

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00144

Gnomad OTH AF: 0.00573

GnomAD3 exomes AF: 0.00144 AC: 358 AN: 248778 Hom.: 1 AF XY: 0.00153 AC XY: 206 AN XY: 134534

Gnomad AFR exome AF: 0.00406

Gnomad AMR exome AF: 0.00101

Gnomad ASJ exome AF: 0.00500

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.000262

Gnomad FIN exome AF: 0.000326

Gnomad NFE exome AF: 0.00162

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.00112 AC: 1625 AN: 1452844 Hom.: 4 Cov.: 32 AF XY: 0.00114 AC XY: 825 AN XY: 720632

Gnomad4 AFR exome AF: 0.00475

Gnomad4 AMR exome AF: 0.00121

Gnomad4 ASJ exome AF: 0.00396

Gnomad4 EAS exome AF: 0.0000761

Gnomad4 SAS exome AF: 0.000325

Gnomad4 FIN exome AF: 0.000678

Gnomad4 NFE exome AF: 0.00102

Gnomad4 OTH exome AF: 0.00144

GnomAD4 genome AF: 0.00222 AC: 338 AN: 152364 Hom.: 0 Cov.: 33 AF XY: 0.00223 AC XY: 166 AN XY: 74518

Gnomad4 AFR AF: 0.00354

Gnomad4 AMR AF: 0.00183

Gnomad4 ASJ AF: 0.00662

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.000659

Gnomad4 NFE AF: 0.00144

Gnomad4 OTH AF: 0.00567

Alfa AF: 0.00108 Hom.: 1

Bravo AF: 0.00220

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00218

EpiControl AF: 0.00350

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 26, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2023	TOP3A: BP4, BP7 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	6.3
DANN	Benign	0.55
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs140837737; hg19: chr17-18180996;