rs1444601

Positions:

• chr3-133611099-G-A
• chr3-133611099-G-T

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_Moderate BP7 BA1

The NM_007027.4(TOPBP1):​c.4078C>T​(p.Leu1360Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.712 in 1,612,022 control chromosomes in the GnomAD database, including 411,088 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 0.72 (39521 hom., cov: 31)
  • Exomes 𝑓: 0.71 (371567 hom.)
• Consequence: TOPBP1 NM_007027.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.502

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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BP7: Synonymous conserved (PhyloP=0.502 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.77 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TOPBP1	NM_007027.4	c.4078C>T	p.Leu1360Leu	synonymous_variant	25/28	ENST00000260810.10	NP_008958.2
TOPBP1	NM_001363889.2	c.4063C>T	p.Leu1355Leu	synonymous_variant	25/28		NP_001350818.1
TOPBP1	XM_017005636.3	c.4078C>T	p.Leu1360Leu	synonymous_variant	25/28		XP_016861125.1
TOPBP1	XM_047447355.1	c.4063C>T	p.Leu1355Leu	synonymous_variant	25/28		XP_047303311.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TOPBP1	ENST00000260810.10	c.4078C>T	p.Leu1360Leu	synonymous_variant	25/28	1	NM_007027.4	ENSP00000260810.5
TOPBP1	ENST00000642236.1	c.4063C>T	p.Leu1355Leu	synonymous_variant	25/28			ENSP00000493612.1

Frequencies

GnomAD3 genomes AF: 0.719 AC: 109169 AN: 151828 Hom.: 39487 Cov.: 31

Gnomad AFR AF: 0.777

Gnomad AMI AF: 0.775

Gnomad AMR AF: 0.679

Gnomad ASJ AF: 0.717

Gnomad EAS AF: 0.597

Gnomad SAS AF: 0.609

Gnomad FIN AF: 0.638

Gnomad MID AF: 0.737

Gnomad NFE AF: 0.721

Gnomad OTH AF: 0.730

GnomAD3 exomes AF: 0.685 AC: 170232 AN: 248338 Hom.: 58955 AF XY: 0.684 AC XY: 92183 AN XY: 134752

Gnomad AFR exome AF: 0.783

Gnomad AMR exome AF: 0.649

Gnomad ASJ exome AF: 0.709

Gnomad EAS exome AF: 0.580

Gnomad SAS exome AF: 0.612

Gnomad FIN exome AF: 0.633

Gnomad NFE exome AF: 0.728

Gnomad OTH exome AF: 0.682

GnomAD4 exome AF: 0.712 AC: 1038963 AN: 1460076 Hom.: 371567 Cov.: 46 AF XY: 0.710 AC XY: 515355 AN XY: 726198

Gnomad4 AFR exome AF: 0.779

Gnomad4 AMR exome AF: 0.653

Gnomad4 ASJ exome AF: 0.709

Gnomad4 EAS exome AF: 0.621

Gnomad4 SAS exome AF: 0.620

Gnomad4 FIN exome AF: 0.640

Gnomad4 NFE exome AF: 0.726

Gnomad4 OTH exome AF: 0.708

GnomAD4 genome AF: 0.719 AC: 109262 AN: 151946 Hom.: 39521 Cov.: 31 AF XY: 0.712 AC XY: 52841 AN XY: 74266

Gnomad4 AFR AF: 0.777

Gnomad4 AMR AF: 0.679

Gnomad4 ASJ AF: 0.717

Gnomad4 EAS AF: 0.596

Gnomad4 SAS AF: 0.607

Gnomad4 FIN AF: 0.638

Gnomad4 NFE AF: 0.721

Gnomad4 OTH AF: 0.730

Alfa AF: 0.721 Hom.: 68683

Bravo AF: 0.728

Asia WGS AF: 0.582 AC: 2023 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
CADD	Benign	3.3
DANN	Benign	0.71

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs1444601; hg19: chr3-133329943; COSMIC: COSV53437748; COSMIC: COSV53437748;