chr22-21963982-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001282112.2(TOP3B):c.1145A>G(p.His382Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0166 in 1,612,800 control chromosomes in the GnomAD database, including 351 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

Frequency

Genomes: 𝑓 0.013 ( 26 hom., cov: 33)

Exomes 𝑓: 0.017 ( 325 hom. )

Consequence

TOP3B
NM_001282112.2 missense

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: 2.32

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 was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005235821).

BP6

Variant 22-21963982-T-C is Benign according to our data. Variant chr22-21963982-T-C is described in ClinVar as [Benign]. Clinvar id is 3060731.Status of the report is no_assertion_criteria_provided, 0 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.013 (1977/152306) while in subpopulation NFE AF = 0.0179 (1215/68000). AF 95% confidence interval is 0.017. There are 26 homozygotes in GnomAd4. There are 907 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position FAILED quality control check.

BS2

High Homozygotes in GnomAd4 at 26 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TOP3B	NM_001282112.2 link	c.1145A>G	p.His382Arg	missense_variant	Exon 11 of 18	ENST00000357179.10	NP_001269041.1	O95985-1A0A024R1C2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TOP3B	ENST00000357179.10 link	c.1145A>G	p.His382Arg	missense_variant	Exon 11 of 18	1	NM_001282112.2	ENSP00000349705.5		O95985-1

Frequencies

GnomAD3 genomes

AF:

0.0130

AC:

1977

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00318

Gnomad AMI

AF:

0.0482

Gnomad AMR

AF:

0.0157

Gnomad ASJ

AF:

0.0729

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00207

Gnomad FIN

AF:

0.00329

Gnomad MID

AF:

0.0316

Gnomad NFE

AF:

0.0179

Gnomad OTH

AF:

0.0187

GnomAD2 exomes

AF:

0.0141

AC:

3508

AN:

249470

AF XY:

0.0140

show subpopulations

Gnomad AFR exome

AF:

0.00271

Gnomad AMR exome

AF:

0.0118

Gnomad ASJ exome

AF:

0.0683

Gnomad EAS exome

AF:

0.0000545

Gnomad FIN exome

AF:

0.00433

Gnomad NFE exome

AF:

0.0185

Gnomad OTH exome

AF:

0.0199

GnomAD4 exome

AF:

0.0169

AC:

24718

AN:

1460494

Hom.:

325

Cov.:

AF XY:

0.0164

AC XY:

11943

AN XY:

726574

show subpopulations

Gnomad4 AFR exome

AF:

0.00227

AC:

AN:

33476

Gnomad4 AMR exome

AF:

0.0127

AC:

567

AN:

44566

Gnomad4 ASJ exome

AF:

0.0705

AC:

1836

AN:

26054

Gnomad4 EAS exome

AF:

0.00

AC:

AN:

39698

Gnomad4 SAS exome

AF:

0.00258

AC:

222

AN:

86122

Gnomad4 FIN exome

AF:

0.00522

AC:

276

AN:

52854

Gnomad4 NFE exome

AF:

0.0184

AC:

20469

AN:

1111626

Gnomad4 Remaining exome

AF:

0.0203

AC:

1226

AN:

60344

Heterozygous variant carriers

1363

2726

4088

5451

6814

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Exome Hom

Variant carriers

786

1572

2358

3144

3930

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0130

AC:

1977

AN:

152306

Hom.:

Cov.:

AF XY:

0.0122

AC XY:

907

AN XY:

74478

show subpopulations

Gnomad4 AFR

AF:

0.00317

AC:

0.00317415

AN:

0.00317415

Gnomad4 AMR

AF:

0.0157

AC:

0.0156842

AN:

0.0156842

Gnomad4 ASJ

AF:

0.0729

AC:

0.0729107

AN:

0.0729107

Gnomad4 EAS

AF:

0.00

AC:

AN:

Gnomad4 SAS

AF:

0.00207

AC:

0.00207039

AN:

0.00207039

Gnomad4 FIN

AF:

0.00329

AC:

0.00329443

AN:

0.00329443

Gnomad4 NFE

AF:

0.0179

AC:

0.0178676

AN:

0.0178676

Gnomad4 OTH

AF:

0.0185

AC:

0.0185009

AN:

0.0185009

Heterozygous variant carriers

193

289

386

482

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Genome Hom

Variant carriers

104

130

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0183

Hom.:

Bravo

AF:

0.0143

TwinsUK

AF:

0.00998

AC:

ALSPAC

AF:

0.0184

AC:

ESP6500AA

AF:

0.00318

AC:

ESP6500EA

AF:

0.0207

AC:

178

ExAC

AF:

0.0134

AC:

1621

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.0183

EpiControl

AF:

0.0209

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

TOP3B-related disorder

Benign:1

Jul 11, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.091

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.54

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.086

T;T

Eigen

Benign

0.060

Eigen_PC

Benign

0.088

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.96

.;D

MetaRNN

Benign

0.0052

T;T

MetaSVM

Benign

-0.83

MutationAssessor

Uncertain

2.0

M;M

PrimateAI

Uncertain

0.70

PROVEAN

Benign

-1.7

N;N

REVEL

Benign

0.048

Sift

Benign

0.57

T;T

Sift4G

Benign

0.63

T;T

Polyphen

0.11

B;B

Vest4

0.21

MPC

0.59

ClinPred

0.017

GERP RS

4.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.23

gMVP

0.48

Mutation Taster

=87/13

polymorphism (auto)

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