rs17301766

Variant names:

Variant summary

Our verdict is Benign. The variant received -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 (★★).

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

Publications

29 publications found

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 Gene-Disease associations (from GenCC):

pulmonary arterial hypertension
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

TOPBP1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
TOPBP1	NM_007027.4 link	c.2450C>T	p.Ser817Leu	missense_variant	Exon 14 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.2450C>T	p.Ser817Leu	missense_variant	Exon 14 of 28	1	NM_007027.4	ENSP00000260810.5		Q92547
TOPBP1	ENST00000642236.1 link	c.2435C>T	p.Ser812Leu	missense_variant	Exon 14 of 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

GnomAD2 exomes

AF:

0.141

AC:

35086

AN:

249120

AF XY:

0.143

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 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

African (AFR)

AF:

0.0706

AC:

2363

AN:

33472

American (AMR)

AF:

0.100

AC:

4487

AN:

44708

Ashkenazi Jewish (ASJ)

AF:

0.153

AC:

3998

AN:

26132

East Asian (EAS)

AF:

0.000428

AC:

AN:

39694

South Asian (SAS)

AF:

0.0675

AC:

5820

AN:

86254

European-Finnish (FIN)

AF:

0.160

AC:

8569

AN:

53400

Middle Eastern (MID)

AF:

0.158

AC:

910

AN:

5764

European-Non Finnish (NFE)

AF:

0.206

AC:

229011

AN:

1111814

Other (OTH)

AF:

0.167

AC:

10104

AN:

60372

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

12876

25753

38629

51506

64382

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.144

AC:

21871

AN:

152152

Hom.:

1891

Cov.:

AF XY:

0.141

AC XY:

10448

AN XY:

74354

show subpopulations

African (AFR)

AF:

0.0755

AC:

3133

AN:

41520

American (AMR)

AF:

0.133

AC:

2033

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.147

AC:

509

AN:

3470

East Asian (EAS)

AF:

0.000385

AC:

AN:

5190

South Asian (SAS)

AF:

0.0636

AC:

306

AN:

4812

European-Finnish (FIN)

AF:

0.172

AC:

1813

AN:

10564

Middle Eastern (MID)

AF:

0.150

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.200

AC:

13601

AN:

67996

Other (OTH)

AF:

0.160

AC:

338

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

952

1903

2855

3806

4758

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.177

Hom.:

7875

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

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jun 19, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Oct 28, 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

0.083

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.57

CADD

Uncertain

(source)

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

PhyloP100

5.5

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

Mutation Taster

=88/12

polymorphism (auto)

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

rs17301766

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over