chr3-133649518-T-C

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_007027.4(TOPBP1):​c.1369A>G​(p.Lys457Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 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: not found (cov: 31)
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07242113).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TOPBP1	NM_007027.4	c.1369A>G	p.Lys457Glu	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>G	p.Lys457Glu	missense_variant	Exon 10 of 28	1	NM_007027.4	ENSP00000260810.5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 67

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.071	.;T
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.44
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.14	T;T
M_CAP	Benign	0.0045	T
MetaRNN	Benign	0.072	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	.;N
PhyloP100		2.5
PrimateAI	Benign	0.32	T
PROVEAN	Benign	0.29	.;N
REVEL	Benign	0.076
Sift	Benign	0.62	.;T
Sift4G	Benign	0.96	.;T
Polyphen		0.0	.;B
Vest4		0.12
MutPred		0.36		.;Loss of ubiquitination at K457 (P = 0.0047);
MVP		0.17
MPC		0.27
ClinPred		0.26	T
GERP RS		4.8
Varity_R		0.10
gMVP		0.18
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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;