rs17301766

Variant names:

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

Variant summary

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

• 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
• Publications: 29 publications found

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

ACMG classification

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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007027.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TOPBP1	NM_007027.4	MANE Select	c.2450C>T	p.Ser817Leu	missense	Exon 14 of 28	NP_008958.2
	TOPBP1	NM_001363889.2		c.2435C>T	p.Ser812Leu	missense	Exon 14 of 28	NP_001350818.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TOPBP1	ENST00000260810.10	TSL:1 MANE Select	c.2450C>T	p.Ser817Leu	missense	Exon 14 of 28	ENSP00000260810.5
	TOPBP1	ENST00000642236.1		c.2435C>T	p.Ser812Leu	missense	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

GnomAD2 exomes AF: 0.141 AC: 35086 AN: 249120 AF XY: 0.143

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

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: 17 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

GnomAD4 genome AF: 0.144 AC: 21871 AN: 152152 Hom.: 1891 Cov.: 32 AF XY: 0.141 AC XY: 10448 AN XY: 74354

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: 2 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: 44 AN: 294

European-Non Finnish (NFE) AF: 0.200 AC: 13601 AN: 67996

Other (OTH) AF: 0.160 AC: 338 AN: 2112

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

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	TOPBP1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

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
MetaRNN	Benign	0.0015	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		5.5
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
Mutation Taster		=88/12	polymorphism (auto)

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

Other links and lift over

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