Variant 22-21957193-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001282112.2(TOP3B):c.2510G>A(p.Arg837Gln) variant causes a missense change. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 27)

Exomes 𝑓: 0.00020 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

TOP3B
NM_001282112.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.47

Variant links:

Genes affected

TOP3B (HGNC:11993): (DNA topoisomerase III beta) 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 relaxing the supercoils and altering the topology of DNA. The enzyme interacts with DNA helicase SGS1 and plays a role in DNA recombination, cellular aging and maintenance of genome stability. Low expression of this gene may be related to higher survival rates in breast cancer patients. This gene has a pseudogene on chromosome 22. Alternate splicing results in multiple transcript variants. Additional alternatively spliced transcript variants of this gene have been described, but their full-length nature is not known. [provided by RefSeq, Aug 2013]

TOP3B links:

PPM1F-AS1 (HGNC:40888): (PPM1F antisense RNA 1)

PPM1F-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.117562205).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TOP3B	NM_001282112.2 linkuse as main transcript	c.2510G>A	p.Arg837Gln	missense_variant	18/18	ENST00000357179.10	NP_001269041.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TOP3B	ENST00000357179.10 linkuse as main transcript	c.2510G>A	p.Arg837Gln	missense_variant	18/18	1	NM_001282112.2	ENSP00000349705	P1	O95985-1
PPM1F-AS1	ENST00000458178.2 linkuse as main transcript	n.17413C>T		non_coding_transcript_exon_variant	2/2	1

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

150376

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.000146

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000213

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000148

Gnomad OTH

AF:

0.000488

GnomAD3 exomes

AF:

0.000139

AC:

AN:

79372

Hom.:

AF XY:

0.000195

AC XY:

AN XY:

41100

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000122

Gnomad SAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000309

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000199

AC:

246

AN:

1234538

Hom.:

Cov.:

AF XY:

0.000205

AC XY:

125

AN XY:

608912

show subpopulations

Gnomad4 AFR exome

AF:

0.0000718

Gnomad4 AMR exome

AF:

0.0000766

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000289

Gnomad4 SAS exome

AF:

0.0000564

Gnomad4 FIN exome

AF:

0.0000639

Gnomad4 NFE exome

AF:

0.000243

Gnomad4 OTH exome

AF:

0.0000386

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000113

AC:

AN:

150494

Hom.:

Cov.:

AF XY:

0.000136

AC XY:

AN XY:

73466

show subpopulations

Gnomad4 AFR

AF:

0.000122

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000214

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000148

Gnomad4 OTH

AF:

0.000483

Alfa

AF:

0.000144

Hom.:

Bravo

AF:

0.000151

ExAC

AF:

0.0000498

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 24, 2024

The c.2510G>A (p.R837Q) alteration is located in exon 18 (coding exon 17) of the TOP3B gene. This alteration results from a G to A substitution at nucleotide position 2510, causing the arginine (R) at amino acid position 837 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.42

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.27

T;T

Eigen

Uncertain

0.30

Eigen_PC

Uncertain

0.32

FATHMM_MKL

Uncertain

0.83

LIST_S2

Uncertain

0.92

.;D

M_CAP

Benign

0.030

MetaRNN

Benign

0.12

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.9

M;M

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.60

PROVEAN

Uncertain

-2.4

N;N

REVEL

Benign

0.12

Sift

Benign

0.30

T;T

Sift4G

Benign

0.091

T;T

Polyphen

0.85

P;P

Vest4

0.15

MutPred

0.31

Loss of methylation at R837 (P = 0.0016);Loss of methylation at R837 (P = 0.0016);

MVP

0.66

MPC

2.3

ClinPred

0.20

GERP RS

4.0

Varity_R

0.092

gMVP

0.43

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