Genetic Variant NM_001282112.2:c.2473G>T (chr22-21957230-C-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001282112.2(TOP3B):c.2473G>T(p.Gly825Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G825S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 27)

Exomes 𝑓: 7.4e-7 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

TOP3B
NM_001282112.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.23

Publications

0 publications found

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: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.2639135).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TOP3B	NM_001282112.2 link	c.2473G>T	p.Gly825Cys	missense_variant	Exon 18 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.2473G>T	p.Gly825Cys	missense_variant	Exon 18 of 18	1	NM_001282112.2	ENSP00000349705.5		O95985-1

Frequencies

GnomAD3 genomes

AF:

0.00000661

AC:

AN:

151232

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000946

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

7.40e-7

AC:

AN:

1351526

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

668762

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30588

American (AMR)

AF:

0.00

AC:

AN:

33720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24562

East Asian (EAS)

AF:

0.00

AC:

AN:

35514

South Asian (SAS)

AF:

0.00

AC:

AN:

77464

European-Finnish (FIN)

AF:

0.0000208

AC:

AN:

48066

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4008

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1041422

Other (OTH)

AF:

0.00

AC:

AN:

56182

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000661

AC:

AN:

151232

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

73802

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41218

American (AMR)

AF:

0.00

AC:

AN:

15192

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3458

East Asian (EAS)

AF:

0.00

AC:

AN:

5016

South Asian (SAS)

AF:

0.00

AC:

AN:

4754

European-Finnish (FIN)

AF:

0.0000946

AC:

AN:

10576

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67734

Other (OTH)

AF:

0.00

AC:

AN:

2062

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.675

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.44

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.42

T;T

Eigen

Benign

-0.34

Eigen_PC

Benign

-0.55

FATHMM_MKL

Benign

0.38

LIST_S2

Benign

0.83

.;T

M_CAP

Benign

0.041

MetaRNN

Benign

0.26

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.7

M;M

PhyloP100

2.2

PrimateAI

Uncertain

0.66

PROVEAN

Uncertain

-3.6

D;D

REVEL

Benign

0.077

Sift

Benign

0.081

T;T

Sift4G

Uncertain

0.0070

D;D

Polyphen

0.97

D;D

Vest4

0.23

MutPred

0.25

Loss of relative solvent accessibility (P = 0.0071);Loss of relative solvent accessibility (P = 0.0071);

MVP

0.66

MPC

2.7

ClinPred

0.95

GERP RS

0.62

Varity_R

0.18

gMVP

0.44

Mutation Taster

=90/10

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over