Variant rs17301766 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_007027.4(TOPBP1):c.2450C>T(p.Ser817Leu) variant causes a missense change. The variant allele was found at a frequency of 0.178 in 1,613,762 control chromosomes in the GnomAD database, including 28,141 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.14 ( 1891 hom., cov: 32)

Exomes 𝑓: 0.18 ( 26250 hom. )

Consequence

TOPBP1
NM_007027.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 5.49

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0015048087).

BP6

Variant 3-133637946-G-A is Benign according to our data. Variant chr3-133637946-G-A is described in ClinVar as [Benign]. Clinvar id is 670995.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.197 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TOPBP1	NM_007027.4 linkuse as main transcript	c.2450C>T	p.Ser817Leu	missense_variant	14/28	ENST00000260810.10	NP_008958.2	Q92547Q05BV8A0AV47A7E2X7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TOPBP1	ENST00000260810.10 linkuse as main transcript	c.2450C>T	p.Ser817Leu	missense_variant	14/28	1	NM_007027.4	ENSP00000260810.5		Q92547
TOPBP1	ENST00000642236.1 linkuse as main transcript	c.2435C>T	p.Ser812Leu	missense_variant	14/28			ENSP00000493612.1		A0A2R8YD63

Frequencies

GnomAD3 genomes

AF:

0.144

AC:

21854

AN:

152034

Hom.:

1888

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0753

Gnomad AMI

AF:

0.101

Gnomad AMR

AF:

0.133

Gnomad ASJ

AF:

0.147

Gnomad EAS

AF:

0.000384

Gnomad SAS

AF:

0.0623

Gnomad FIN

AF:

0.172

Gnomad MID

AF:

0.152

Gnomad NFE

AF:

0.200

Gnomad OTH

AF:

0.162

GnomAD3 exomes

AF:

0.141

AC:

35086

AN:

249120

Hom.:

3101

AF XY:

0.143

AC XY:

19316

AN XY:

135146

show subpopulations

Gnomad AFR exome

AF:

0.0742

Gnomad AMR exome

AF:

0.0952

Gnomad ASJ exome

AF:

0.157

Gnomad EAS exome

AF:

0.000557

Gnomad SAS exome

AF:

0.0660

Gnomad FIN exome

AF:

0.159

Gnomad NFE exome

AF:

0.200

Gnomad OTH exome

AF:

0.164

GnomAD4 exome

AF:

0.181

AC:

265279

AN:

1461610

Hom.:

26250

Cov.:

AF XY:

0.179

AC XY:

129832

AN XY:

727096

show subpopulations

Gnomad4 AFR exome

AF:

0.0706

Gnomad4 AMR exome

AF:

0.100

Gnomad4 ASJ exome

AF:

0.153

Gnomad4 EAS exome

AF:

0.000428

Gnomad4 SAS exome

AF:

0.0675

Gnomad4 FIN exome

AF:

0.160

Gnomad4 NFE exome

AF:

0.206

Gnomad4 OTH exome

AF:

0.167

GnomAD4 genome

AF:

0.144

AC:

21871

AN:

152152

Hom.:

1891

Cov.:

AF XY:

0.141

AC XY:

10448

AN XY:

74354

show subpopulations

Gnomad4 AFR

AF:

0.0755

Gnomad4 AMR

AF:

0.133

Gnomad4 ASJ

AF:

0.147

Gnomad4 EAS

AF:

0.000385

Gnomad4 SAS

AF:

0.0636

Gnomad4 FIN

AF:

0.172

Gnomad4 NFE

AF:

0.200

Gnomad4 OTH

AF:

0.160

Alfa

AF:

0.184

Hom.:

5887

Bravo

AF:

0.140

TwinsUK

AF:

0.218

AC:

807

ALSPAC

AF:

0.214

AC:

824

ESP6500AA

AF:

0.0730

AC:

293

ESP6500EA

AF:

0.195

AC:

1628

ExAC

AF:

0.141

AC:

17039

Asia WGS

AF:

0.0380

AC:

131

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 19, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

TOPBP1-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 28, 2019

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

0.083

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.57

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.32

.;T

Eigen

Benign

0.086

Eigen_PC

Benign

0.21

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.84

T;T

MetaRNN

Benign

0.0015

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.7

.;M

PrimateAI

Benign

0.48

PROVEAN

Uncertain

-2.5

.;D

REVEL

Benign

0.060

Sift

Uncertain

0.0040

.;D

Sift4G

Benign

0.087

.;T

Polyphen

0.37

.;B

Vest4

0.055

MPC

0.18

ClinPred

0.041

GERP RS

5.2

Varity_R

0.13

gMVP

0.37

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