3-133616943-C-T

Variant names:

• chr3-133616943-C-T
• rs3732574
• NM_007027.4:c.3760-18G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_007027.4(TOPBP1):​c.3760-18G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.705 in 1,438,384 control chromosomes in the GnomAD database, including 359,859 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.67 (34660 hom., cov: 32)
  • Exomes 𝑓: 0.71 (325199 hom.)
• Consequence: TOPBP1 NM_007027.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.817
• Publications: 13 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.716 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TOPBP1	NM_007027.4	c.3760-18G>A		intron_variant	Intron 22 of 27	ENST00000260810.10	NP_008958.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TOPBP1	ENST00000260810.10	c.3760-18G>A		intron_variant	Intron 22 of 27	1	NM_007027.4	ENSP00000260810.5
TOPBP1	ENST00000642236.1	c.3745-18G>A		intron_variant	Intron 22 of 27			ENSP00000493612.1
TOPBP1	ENST00000505804.1	n.368-18G>A		intron_variant	Intron 1 of 1	2

Frequencies

GnomAD3 genomes AF: 0.674 AC: 102305 AN: 151834 Hom.: 34634 Cov.: 32

Gnomad AFR AF: 0.620

Gnomad AMI AF: 0.773

Gnomad AMR AF: 0.659

Gnomad ASJ AF: 0.716

Gnomad EAS AF: 0.598

Gnomad SAS AF: 0.609

Gnomad FIN AF: 0.639

Gnomad MID AF: 0.737

Gnomad NFE AF: 0.721

Gnomad OTH AF: 0.699

GnomAD2 exomes AF: 0.672 AC: 67421 AN: 100294 AF XY: 0.672

Gnomad AFR exome AF: 0.628

Gnomad AMR exome AF: 0.641

Gnomad ASJ exome AF: 0.713

Gnomad EAS exome AF: 0.581

Gnomad FIN exome AF: 0.628

Gnomad NFE exome AF: 0.728

Gnomad OTH exome AF: 0.670

GnomAD4 exome AF: 0.709 AC: 912293 AN: 1286432 Hom.: 325199 Cov.: 19 AF XY: 0.708 AC XY: 449834 AN XY: 635580

African (AFR) AF: 0.618 AC: 16991 AN: 27490

American (AMR) AF: 0.646 AC: 12355 AN: 19136

Ashkenazi Jewish (ASJ) AF: 0.708 AC: 14905 AN: 21048

East Asian (EAS) AF: 0.625 AC: 21579 AN: 34510

South Asian (SAS) AF: 0.619 AC: 40948 AN: 66172

European-Finnish (FIN) AF: 0.638 AC: 28780 AN: 45096

Middle Eastern (MID) AF: 0.735 AC: 3715 AN: 5054

European-Non Finnish (NFE) AF: 0.725 AC: 735695 AN: 1014384

Other (OTH) AF: 0.697 AC: 37325 AN: 53542

GnomAD4 genome AF: 0.674 AC: 102383 AN: 151952 Hom.: 34660 Cov.: 32 AF XY: 0.668 AC XY: 49629 AN XY: 74256

African (AFR) AF: 0.620 AC: 25676 AN: 41396

American (AMR) AF: 0.659 AC: 10069 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.716 AC: 2486 AN: 3472

East Asian (EAS) AF: 0.597 AC: 3089 AN: 5172

South Asian (SAS) AF: 0.608 AC: 2926 AN: 4814

European-Finnish (FIN) AF: 0.639 AC: 6733 AN: 10544

Middle Eastern (MID) AF: 0.735 AC: 216 AN: 294

European-Non Finnish (NFE) AF: 0.721 AC: 49005 AN: 67964

Other (OTH) AF: 0.699 AC: 1478 AN: 2114

Alfa AF: 0.689 Hom.: 6598

Bravo AF: 0.675

Asia WGS AF: 0.575 AC: 1999 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	15
DANN	Benign	0.58
PhyloP100		0.82
Mutation Taster		=100/0	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: rs3732574; hg19: chr3-133335787; COSMIC: COSV53439430; COSMIC: COSV53439430;