17-18274863-C-T

Variant names:

• chr17-18274863-C-T
• rs765404592
• NM_004618.5:c.2945G>A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_004618.5(TOP3A):​c.2945G>A​(p.Arg982Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000472 in 1,461,890 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.000047 (0 hom.)
• Consequence: TOP3A NM_004618.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.29

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.37853646).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TOP3A	NM_004618.5	c.2945G>A	p.Arg982Gln	missense_variant	Exon 19 of 19	ENST00000321105.10	NP_004609.1
TOP3A	NM_001320759.2	c.2660G>A	p.Arg887Gln	missense_variant	Exon 18 of 18		NP_001307688.1
TOP3A	XM_047436633.1	c.2024G>A	p.Arg675Gln	missense_variant	Exon 17 of 17		XP_047292589.1
TOP3A	XM_047436634.1	c.2024G>A	p.Arg675Gln	missense_variant	Exon 17 of 17		XP_047292590.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TOP3A	ENST00000321105.10	c.2945G>A	p.Arg982Gln	missense_variant	Exon 19 of 19	1	NM_004618.5	ENSP00000321636.5

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD3 exomes AF: 0.000123 AC: 31 AN: 251490 Hom.: 0 AF XY: 0.000110 AC XY: 15 AN XY: 135918

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000636

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.000977

GnomAD4 exome AF: 0.0000472 AC: 69 AN: 1461890 Hom.: 0 Cov.: 31 AF XY: 0.0000495 AC XY: 36 AN XY: 727248

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000604

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000360

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 30

Bravo AF: 0.0000793

ExAC AF: 0.000148 AC: 18

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Dec 30, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 982 of the TOP3A protein (p.Arg982Gln). This variant is present in population databases (rs765404592, gnomAD 0.06%). This variant has not been reported in the literature in individuals affected with TOP3A-related conditions. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.12
CADD	Pathogenic	32
DANN	Uncertain	0.99
DEOGEN2	Benign	0.30	T;T;.
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.38	T;T;T
MetaSVM	Uncertain	0.38	D
MutationAssessor	Uncertain	2.8	M;M;.
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-2.9	.;D;.
REVEL	Uncertain	0.37
Sift	Uncertain	0.0040	.;D;.
Sift4G	Uncertain	0.050	T;T;.
Polyphen		1.0	D;D;.
Vest4		0.55
MutPred		0.56		Loss of MoRF binding (P = 0.0188);Loss of MoRF binding (P = 0.0188);.;
MVP		0.22
MPC		0.70
ClinPred		0.92	D
GERP RS		5.5
Varity_R		0.26
gMVP		0.57

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: rs765404592; hg19: chr17-18178177;