3-133649518-T-G

Variant names:

• chr3-133649518-T-G
• rs3192149
• NM_007027.4:c.1369A>C

Variant summary

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

The NM_007027.4(TOPBP1):​c.1369A>C​(p.Lys457Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.744 in 1,613,580 control chromosomes in the GnomAD database, including 448,545 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.74 (42049 hom., cov: 31)
  • Exomes 𝑓: 0.74 (406496 hom.)
• Consequence: TOPBP1 NM_007027.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.53
• Publications: 44 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 (MetaRNN=8.155077E-7).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.781 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TOPBP1	NM_007027.4	c.1369A>C	p.Lys457Gln	missense_variant	Exon 10 of 28	ENST00000260810.10	NP_008958.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TOPBP1	ENST00000260810.10	c.1369A>C	p.Lys457Gln	missense_variant	Exon 10 of 28	1	NM_007027.4	ENSP00000260810.5

Frequencies

GnomAD3 genomes AF: 0.741 AC: 112589 AN: 151908 Hom.: 42015 Cov.: 31

Gnomad AFR AF: 0.788

Gnomad AMI AF: 0.775

Gnomad AMR AF: 0.687

Gnomad ASJ AF: 0.742

Gnomad EAS AF: 0.597

Gnomad SAS AF: 0.645

Gnomad FIN AF: 0.656

Gnomad MID AF: 0.788

Gnomad NFE AF: 0.755

Gnomad OTH AF: 0.753

GnomAD2 exomes AF: 0.711 AC: 176854 AN: 248800 AF XY: 0.711

Gnomad AFR exome AF: 0.794

Gnomad AMR exome AF: 0.658

Gnomad ASJ exome AF: 0.737

Gnomad EAS exome AF: 0.580

Gnomad FIN exome AF: 0.655

Gnomad NFE exome AF: 0.760

Gnomad OTH exome AF: 0.707

GnomAD4 exome AF: 0.744 AC: 1087448 AN: 1461554 Hom.: 406496 Cov.: 67 AF XY: 0.742 AC XY: 539718 AN XY: 727046

African (AFR) AF: 0.789 AC: 26417 AN: 33476

American (AMR) AF: 0.661 AC: 29554 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.738 AC: 19292 AN: 26132

East Asian (EAS) AF: 0.621 AC: 24628 AN: 39680

South Asian (SAS) AF: 0.661 AC: 57026 AN: 86254

European-Finnish (FIN) AF: 0.661 AC: 35251 AN: 53350

Middle Eastern (MID) AF: 0.766 AC: 4418 AN: 5766

European-Non Finnish (NFE) AF: 0.761 AC: 846504 AN: 1111802

Other (OTH) AF: 0.735 AC: 44358 AN: 60370

GnomAD4 genome AF: 0.741 AC: 112682 AN: 152026 Hom.: 42049 Cov.: 31 AF XY: 0.732 AC XY: 54429 AN XY: 74308

African (AFR) AF: 0.788 AC: 32672 AN: 41472

American (AMR) AF: 0.688 AC: 10501 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.742 AC: 2573 AN: 3468

East Asian (EAS) AF: 0.597 AC: 3076 AN: 5154

South Asian (SAS) AF: 0.644 AC: 3098 AN: 4812

European-Finnish (FIN) AF: 0.656 AC: 6926 AN: 10558

Middle Eastern (MID) AF: 0.789 AC: 232 AN: 294

European-Non Finnish (NFE) AF: 0.755 AC: 51310 AN: 67976

Other (OTH) AF: 0.752 AC: 1589 AN: 2112

Alfa AF: 0.752 Hom.: 165818

Bravo AF: 0.748

TwinsUK AF: 0.753 AC: 2792

ALSPAC AF: 0.764 AC: 2946

ESP6500AA AF: 0.786 AC: 2902

ESP6500EA AF: 0.767 AC: 6273

ExAC AF: 0.716 AC: 86439

Asia WGS AF: 0.593 AC: 2063 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.81	T
BayesDel_noAF	Benign	-0.79
CADD	Benign	17
DANN	Benign	0.15
DEOGEN2	Benign	0.050	.;T
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.47
FATHMM_MKL	Benign	0.041	N
LIST_S2	Benign	0.10	T;T
MetaRNN	Benign	8.2e-7	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.3	.;N
PhyloP100		2.5
PrimateAI	Benign	0.32	T
PROVEAN	Benign	0.89	.;N
REVEL	Benign	0.098
Sift	Benign	1.0	.;T
Sift4G	Benign	1.0	.;T
Polyphen		0.0	.;B
Vest4		0.020
MPC		0.21
ClinPred		0.0044	T
GERP RS		4.8
Varity_R		0.071
gMVP		0.16
Mutation Taster		=96/4	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs3192149; hg19: chr3-133368362; COSMIC: COSV53439449; COSMIC: COSV53439449;