chr3-133611099-G-T

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_007027.4(TOPBP1):​c.4078C>A​(p.Leu1360Met) 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. 14/22 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: 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.41735685).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007027.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TOPBP1	NM_007027.4	MANE Select	c.4078C>A	p.Leu1360Met	missense	Exon 25 of 28	NP_008958.2	Q92547
	TOPBP1	NM_001363889.2		c.4063C>A	p.Leu1355Met	missense	Exon 25 of 28	NP_001350818.1	A0A2R8YD63

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TOPBP1	ENST00000260810.10	TSL:1 MANE Select	c.4078C>A	p.Leu1360Met	missense	Exon 25 of 28	ENSP00000260810.5	Q92547
	TOPBP1	ENST00000881661.1		c.4078C>A	p.Leu1360Met	missense	Exon 25 of 28	ENSP00000551720.1
	TOPBP1	ENST00000953681.1		c.4078C>A	p.Leu1360Met	missense	Exon 25 of 28	ENSP00000623740.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 46

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.037	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.18	T
Eigen	Benign	-0.12
Eigen_PC	Benign	-0.16
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.76	T
M_CAP	Benign	0.053	D
MetaRNN	Benign	0.42	T
MetaSVM	Benign	-0.69	T
MutationAssessor	Pathogenic	3.0	M
PhyloP100		0.50
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-0.66	N
REVEL	Benign	0.22
Sift	Benign	0.11	T
Sift4G	Benign	0.12	T
Polyphen		0.94	P
Vest4		0.44
MutPred		0.45		Gain of catalytic residue at L1360 (P = 0.0648)
MVP		0.42
MPC		0.65
ClinPred		0.98	D
GERP RS		0.38
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.27
gMVP		0.32
Mutation Taster		=81/19	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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;