rs1444601

Variant names:

• chr3-133611099-G-A
• rs1444601
• NM_007027.4:c.4078C>T

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 32 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 -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 rank	MANE	Protein	UniProt
TOPBP1	NM_007027.4	c.4078C>T	p.Leu1360Leu	synonymous_variant	Exon 25 of 28	ENST00000260810.10	NP_008958.2
TOPBP1	NM_001363889.2	c.4063C>T	p.Leu1355Leu	synonymous_variant	Exon 25 of 28		NP_001350818.1
TOPBP1	XM_017005636.3	c.4078C>T	p.Leu1360Leu	synonymous_variant	Exon 25 of 28		XP_016861125.1
TOPBP1	XM_047447355.1	c.4063C>T	p.Leu1355Leu	synonymous_variant	Exon 25 of 28		XP_047303311.1

Ensembl

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

GnomAD2 exomes AF: 0.685 AC: 170232 AN: 248338 AF XY: 0.684

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 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

African (AFR) AF: 0.779 AC: 26036 AN: 33440

American (AMR) AF: 0.653 AC: 29034 AN: 44496

Ashkenazi Jewish (ASJ) AF: 0.709 AC: 18484 AN: 26084

East Asian (EAS) AF: 0.621 AC: 24619 AN: 39660

South Asian (SAS) AF: 0.620 AC: 53273 AN: 85962

European-Finnish (FIN) AF: 0.640 AC: 34101 AN: 53322

Middle Eastern (MID) AF: 0.740 AC: 4265 AN: 5766

European-Non Finnish (NFE) AF: 0.726 AC: 806462 AN: 1111042

Other (OTH) AF: 0.708 AC: 42689 AN: 60304

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

African (AFR) AF: 0.777 AC: 32200 AN: 41430

American (AMR) AF: 0.679 AC: 10360 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.717 AC: 2486 AN: 3468

East Asian (EAS) AF: 0.596 AC: 3074 AN: 5158

South Asian (SAS) AF: 0.607 AC: 2924 AN: 4816

European-Finnish (FIN) AF: 0.638 AC: 6719 AN: 10532

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

European-Non Finnish (NFE) AF: 0.721 AC: 49037 AN: 67976

Other (OTH) AF: 0.730 AC: 1541 AN: 2110

Alfa AF: 0.721 Hom.: 92504

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
PhyloP100		0.50
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1444601; hg19: chr3-133329943; COSMIC: COSV53437748; COSMIC: COSV53437748;