Variant chr17-18274863-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

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

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.29

Variant links:

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 links:

TOP3A (HGNC:):

TOP3A links:

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ACMG classification

Classification made for transcript

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/exons	MANE	Protein	UniProt
TOP3A	NM_004618.5 linkuse as main transcript	c.2945G>A	p.Arg982Gln	missense_variant	19/19	ENST00000321105.10	NP_004609.1	Q13472-1
TOP3A	NM_001320759.2 linkuse as main transcript	c.2660G>A	p.Arg887Gln	missense_variant	18/18		NP_001307688.1	Q13472-3
TOP3A	XM_047436633.1 linkuse as main transcript	c.2024G>A	p.Arg675Gln	missense_variant	17/17		XP_047292589.1
TOP3A	XM_047436634.1 linkuse as main transcript	c.2024G>A	p.Arg675Gln	missense_variant	17/17		XP_047292590.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TOP3A	ENST00000321105.10 linkuse as main transcript	c.2945G>A	p.Arg982Gln	missense_variant	19/19	1	NM_004618.5	ENSP00000321636.5		Q13472-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.000123

AC:

AN:

251490

Hom.:

AF XY:

0.000110

AC XY:

AN XY:

135918

show subpopulations

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:

AN:

1461890

Hom.:

Cov.:

AF XY:

0.0000495

AC XY:

AN XY:

727248

show subpopulations

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.:

Bravo

AF:

0.0000793

ExAC

AF:

0.000148

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 30, 2023

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

BayesDel_noAF

Benign

-0.12

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Benign

0.30

T;T;.

Eigen

Pathogenic

0.82

Eigen_PC

Pathogenic

0.79

FATHMM_MKL

Pathogenic

0.99

M_CAP

Benign

0.045

MetaRNN

Benign

0.38

T;T;T

MetaSVM

Uncertain

0.38

MutationAssessor

Uncertain

2.8

M;M;.

PrimateAI

Uncertain

0.50

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over