Variant rs10935070 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BA1

The ENST00000260810.10(TOPBP1):c.3125A>G(p.Asn1042Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.299 in 1,608,256 control chromosomes in the GnomAD database, including 77,814 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.23 ( 5322 hom., cov: 32)

Exomes 𝑓: 0.31 ( 72492 hom. )

Consequence

TOPBP1
ENST00000260810.10 missense

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: -2.08

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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.001906991).

BP6

Variant 3-133623144-T-C is Benign according to our data. Variant chr3-133623144-T-C is described in ClinVar as [Benign]. Clinvar id is 3059833.Status of the report is no_assertion_criteria_provided, 0 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.34 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.3125A>G	p.Asn1042Ser	missense_variant	19/28	ENST00000260810.10	NP_008958.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
TOPBP1	ENST00000260810.10 linkuse as main transcript	c.3125A>G	p.Asn1042Ser	missense_variant	19/28	1	NM_007027.4	ENSP00000260810	P4
TOPBP1	ENST00000513818.1 linkuse as main transcript	n.351A>G		non_coding_transcript_exon_variant	4/6	1
TOPBP1	ENST00000642236.1 linkuse as main transcript	c.3110A>G	p.Asn1037Ser	missense_variant	19/28			ENSP00000493612	A2

Frequencies

GnomAD3 genomes

AF:

0.231

AC:

35196

AN:

152050

Hom.:

5317

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0594

Gnomad AMI

AF:

0.280

Gnomad AMR

AF:

0.298

Gnomad ASJ

AF:

0.338

Gnomad EAS

AF:

0.0217

Gnomad SAS

AF:

0.355

Gnomad FIN

AF:

0.227

Gnomad MID

AF:

0.313

Gnomad NFE

AF:

0.322

Gnomad OTH

AF:

0.264

GnomAD3 exomes

AF:

0.288

AC:

71361

AN:

248120

Hom.:

11817

AF XY:

0.296

AC XY:

39843

AN XY:

134672

show subpopulations

Gnomad AFR exome

AF:

0.0527

Gnomad AMR exome

AF:

0.353

Gnomad ASJ exome

AF:

0.333

Gnomad EAS exome

AF:

0.0173

Gnomad SAS exome

AF:

0.366

Gnomad FIN exome

AF:

0.233

Gnomad NFE exome

AF:

0.328

Gnomad OTH exome

AF:

0.293

GnomAD4 exome

AF:

0.306

AC:

445995

AN:

1456088

Hom.:

72492

Cov.:

AF XY:

0.310

AC XY:

224678

AN XY:

724586

show subpopulations

Gnomad4 AFR exome

AF:

0.0477

Gnomad4 AMR exome

AF:

0.346

Gnomad4 ASJ exome

AF:

0.331

Gnomad4 EAS exome

AF:

0.0205

Gnomad4 SAS exome

AF:

0.374

Gnomad4 FIN exome

AF:

0.242

Gnomad4 NFE exome

AF:

0.321

Gnomad4 OTH exome

AF:

0.289

GnomAD4 genome

AF:

0.231

AC:

35197

AN:

152168

Hom.:

5322

Cov.:

AF XY:

0.231

AC XY:

17156

AN XY:

74398

show subpopulations

Gnomad4 AFR

AF:

0.0592

Gnomad4 AMR

AF:

0.299

Gnomad4 ASJ

AF:

0.338

Gnomad4 EAS

AF:

0.0218

Gnomad4 SAS

AF:

0.354

Gnomad4 FIN

AF:

0.227

Gnomad4 NFE

AF:

0.322

Gnomad4 OTH

AF:

0.262

Alfa

AF:

0.302

Hom.:

13969

Bravo

AF:

0.226

TwinsUK

AF:

0.309

AC:

1147

ALSPAC

AF:

0.319

AC:

1229

ESP6500AA

AF:

0.0588

AC:

212

ESP6500EA

AF:

0.327

AC:

2657

ExAC

AF:

0.287

AC:

34693

Asia WGS

AF:

0.183

AC:

636

AN:

3474

EpiCase

AF:

0.328

EpiControl

AF:

0.325

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

TOPBP1-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 18, 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

0.054

BayesDel_addAF

Benign

-0.86

BayesDel_noAF

Benign

-0.87

CADD

Benign

0.0030

DANN

Benign

0.44

DEOGEN2

Benign

0.069

.;T

Eigen

Benign

-1.8

Eigen_PC

Benign

-1.9

FATHMM_MKL

Benign

0.0068

LIST_S2

Benign

0.56

T;T

MetaRNN

Benign

0.0019

T;T

MetaSVM

Benign

-0.92

MutationAssessor

Benign

-0.77

.;N

MutationTaster

Benign

1.0

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.37

.;N

REVEL

Benign

0.19

Sift

Benign

0.31

.;T

Sift4G

Benign

0.44

.;T

Polyphen

0.0

.;B

Vest4

0.015

MPC

0.15

ClinPred

0.034

GERP RS

-9.4

Varity_R

0.013

gMVP

0.12

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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