Genetic Variant TOPBP1:p.Lys457Gln (chr3-133649518-T-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_007027.4(TOPBP1):c.1369A>C(p.Lys457Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.744 in 1,613,580 control chromosomes in the GnomAD database, including 448,545 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.74 ( 42049 hom., cov: 31)

Exomes 𝑓: 0.74 ( 406496 hom. )

Consequence

TOPBP1
NM_007027.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.53

Variant links:

Genes affected

TOPBP1 (HGNC:17008): (DNA topoisomerase II binding protein 1) This gene encodes a binding protein which interacts with the C-terminal region of topoisomerase II beta. This interaction suggests a supportive role for this protein in the catalytic reactions of topoisomerase II beta through transient breakages of DNA strands. [provided by RefSeq, Jul 2008]

TOPBP1 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=8.155077E-7).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.781 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TOPBP1	NM_007027.4 link	c.1369A>C	p.Lys457Gln	missense_variant	Exon 10 of 28	ENST00000260810.10	NP_008958.2	Q92547Q05BV8A0AV47A7E2X7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TOPBP1	ENST00000260810.10 link	c.1369A>C	p.Lys457Gln	missense_variant	Exon 10 of 28	1	NM_007027.4	ENSP00000260810.5		Q92547

Frequencies

GnomAD3 genomes

AF:

0.741

AC:

112589

AN:

151908

Hom.:

42015

Cov.:

show subpopulations

Gnomad AFR

AF:

0.788

Gnomad AMI

AF:

0.775

Gnomad AMR

AF:

0.687

Gnomad ASJ

AF:

0.742

Gnomad EAS

AF:

0.597

Gnomad SAS

AF:

0.645

Gnomad FIN

AF:

0.656

Gnomad MID

AF:

0.788

Gnomad NFE

AF:

0.755

Gnomad OTH

AF:

0.753

GnomAD3 exomes

AF:

0.711

AC:

176854

AN:

248800

Hom.:

63516

AF XY:

0.711

AC XY:

96024

AN XY:

134990

show subpopulations

Gnomad AFR exome

AF:

0.794

Gnomad AMR exome

AF:

0.658

Gnomad ASJ exome

AF:

0.737

Gnomad EAS exome

AF:

0.580

Gnomad SAS exome

AF:

0.655

Gnomad FIN exome

AF:

0.655

Gnomad NFE exome

AF:

0.760

Gnomad OTH exome

AF:

0.707

GnomAD4 exome

AF:

0.744

AC:

1087448

AN:

1461554

Hom.:

406496

Cov.:

AF XY:

0.742

AC XY:

539718

AN XY:

727046

show subpopulations

Gnomad4 AFR exome

AF:

0.789

Gnomad4 AMR exome

AF:

0.661

Gnomad4 ASJ exome

AF:

0.738

Gnomad4 EAS exome

AF:

0.621

Gnomad4 SAS exome

AF:

0.661

Gnomad4 FIN exome

AF:

0.661

Gnomad4 NFE exome

AF:

0.761

Gnomad4 OTH exome

AF:

0.735

GnomAD4 genome

AF:

0.741

AC:

112682

AN:

152026

Hom.:

42049

Cov.:

AF XY:

0.732

AC XY:

54429

AN XY:

74308

show subpopulations

Gnomad4 AFR

AF:

0.788

Gnomad4 AMR

AF:

0.688

Gnomad4 ASJ

AF:

0.742

Gnomad4 EAS

AF:

0.597

Gnomad4 SAS

AF:

0.644

Gnomad4 FIN

AF:

0.656

Gnomad4 NFE

AF:

0.755

Gnomad4 OTH

AF:

0.752

Alfa

AF:

0.751

Hom.:

110934

Bravo

AF:

0.748

TwinsUK

AF:

0.753

AC:

2792

ALSPAC

AF:

0.764

AC:

2946

ESP6500AA

AF:

0.786

AC:

2902

ESP6500EA

AF:

0.767

AC:

6273

ExAC

AF:

0.716

AC:

86439

Asia WGS

AF:

0.593

AC:

2063

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.064

BayesDel_addAF

Benign

-0.81

BayesDel_noAF

Benign

-0.79

CADD

Benign

DANN

Benign

0.15

DEOGEN2

Benign

0.050

.;T

Eigen

Benign

-0.77

Eigen_PC

Benign

-0.47

FATHMM_MKL

Benign

0.041

LIST_S2

Benign

0.10

T;T

MetaRNN

Benign

8.2e-7

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-1.3

.;N

PrimateAI

Benign

0.32

PROVEAN

Benign

0.89

.;N

REVEL

Benign

0.098

Sift

Benign

1.0

.;T

Sift4G

Benign

1.0

.;T

Polyphen

0.0

.;B

Vest4

0.020

MPC

0.21

ClinPred

0.0044

GERP RS

4.8

Varity_R

0.071

gMVP

0.16

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over