rs17301766

Variant names:

• chr3-133637946-G-A
• rs17301766
• NM_007027.4:c.2450C>T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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 the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: 𝑓 0.14 (1891 hom., cov: 32)
  • Exomes 𝑓: 0.18 (26250 hom.)
• Consequence: TOPBP1 NM_007027.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 5.49

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]

ACMG classification

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 rank	MANE	Protein	UniProt
TOPBP1	NM_007027.4	c.2450C>T	p.Ser817Leu	missense_variant	Exon 14 of 28	ENST00000260810.10	NP_008958.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TOPBP1	ENST00000260810.10	c.2450C>T	p.Ser817Leu	missense_variant	Exon 14 of 28	1	NM_007027.4	ENSP00000260810.5
TOPBP1	ENST00000642236.1	c.2435C>T	p.Ser812Leu	missense_variant	Exon 14 of 28			ENSP00000493612.1

Frequencies

GnomAD3 genomes AF: 0.144 AC: 21854 AN: 152034 Hom.: 1888 Cov.: 32

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

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.: 33 AF XY: 0.179 AC XY: 129832 AN XY: 727096

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.: 32 AF XY: 0.141 AC XY: 10448 AN XY: 74354

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

Submissions by phenotype

not provided Benign:2

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. -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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	T
BayesDel_noAF	Benign	-0.57
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.32	.;T
Eigen	Benign	0.086
Eigen_PC	Benign	0.21
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.84	T;T
MetaRNN	Benign	0.0015	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.7	.;M
PrimateAI	Benign	0.48	T
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	T
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

Other links and lift over

dbSNP: rs17301766; hg19: chr3-133356790; COSMIC: COSV53442711;