NM_007027.4:c.3125A>G

Variant names:

• chr3-133623144-T-C
• rs10935070
• NM_007027.4:c.3125A>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_007027.4(TOPBP1):​c.3125A>G​(p.Asn1042Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.299 in 1,608,256 control chromosomes in the GnomAD database, including 77,814 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.23 (5322 hom., cov: 32)
  • Exomes 𝑓: 0.31 (72492 hom.)
• Consequence: TOPBP1 NM_007027.4 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: -2.08
• Publications: 34 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.001906991).
• BP6: Variant 3-133623144-T-C is Benign according to our data. Variant chr3-133623144-T-C is described in ClinVar as Benign. ClinVar VariationId is 3059833.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.34 is higher than 0.05.

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.3125A>G	p.Asn1042Ser	missense	Exon 19 of 28	NP_008958.2	Q92547
	TOPBP1	NM_001363889.2		c.3110A>G	p.Asn1037Ser	missense	Exon 19 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.3125A>G	p.Asn1042Ser	missense	Exon 19 of 28	ENSP00000260810.5	Q92547
	TOPBP1	ENST00000513818.1	TSL:1	n.351A>G		non_coding_transcript_exon	Exon 4 of 6
	TOPBP1	ENST00000881661.1		c.3125A>G	p.Asn1042Ser	missense	Exon 19 of 28	ENSP00000551720.1

Frequencies

GnomAD3 genomes AF: 0.231 AC: 35196 AN: 152050 Hom.: 5317 Cov.: 32

Gnomad AFR AF: 0.0594

Gnomad AMI AF: 0.280

Gnomad AMR AF: 0.298

Gnomad ASJ AF: 0.338

Gnomad EAS AF: 0.0217

Gnomad SAS AF: 0.355

Gnomad FIN AF: 0.227

Gnomad MID AF: 0.313

Gnomad NFE AF: 0.322

Gnomad OTH AF: 0.264

GnomAD2 exomes AF: 0.288 AC: 71361 AN: 248120 AF XY: 0.296

Gnomad AFR exome AF: 0.0527

Gnomad AMR exome AF: 0.353

Gnomad ASJ exome AF: 0.333

Gnomad EAS exome AF: 0.0173

Gnomad FIN exome AF: 0.233

Gnomad NFE exome AF: 0.328

Gnomad OTH exome AF: 0.293

GnomAD4 exome AF: 0.306 AC: 445995 AN: 1456088 Hom.: 72492 Cov.: 32 AF XY: 0.310 AC XY: 224678 AN XY: 724586

African (AFR) AF: 0.0477 AC: 1594 AN: 33436

American (AMR) AF: 0.346 AC: 15407 AN: 44546

Ashkenazi Jewish (ASJ) AF: 0.331 AC: 8644 AN: 26078

East Asian (EAS) AF: 0.0205 AC: 815 AN: 39662

South Asian (SAS) AF: 0.374 AC: 32140 AN: 85966

European-Finnish (FIN) AF: 0.242 AC: 12924 AN: 53350

Middle Eastern (MID) AF: 0.344 AC: 1944 AN: 5650

European-Non Finnish (NFE) AF: 0.321 AC: 355155 AN: 1107260

Other (OTH) AF: 0.289 AC: 17372 AN: 60140

GnomAD4 genome AF: 0.231 AC: 35197 AN: 152168 Hom.: 5322 Cov.: 32 AF XY: 0.231 AC XY: 17156 AN XY: 74398

African (AFR) AF: 0.0592 AC: 2461 AN: 41544

American (AMR) AF: 0.299 AC: 4561 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.338 AC: 1172 AN: 3468

East Asian (EAS) AF: 0.0218 AC: 113 AN: 5188

South Asian (SAS) AF: 0.354 AC: 1703 AN: 4814

European-Finnish (FIN) AF: 0.227 AC: 2401 AN: 10570

Middle Eastern (MID) AF: 0.306 AC: 90 AN: 294

European-Non Finnish (NFE) AF: 0.322 AC: 21890 AN: 67996

Other (OTH) AF: 0.262 AC: 552 AN: 2110

Alfa AF: 0.293 Hom.: 27511

Bravo AF: 0.226

TwinsUK AF: 0.309 AC: 1147

ALSPAC AF: 0.319 AC: 1229

ESP6500AA AF: 0.0588 AC: 212

ESP6500EA AF: 0.327 AC: 2657

ExAC AF: 0.287 AC: 34693

Asia WGS AF: 0.183 AC: 636 AN: 3474

EpiCase AF: 0.328

EpiControl AF: 0.325

ClinVar

ClinVar submissions

Significance: Benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	TOPBP1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.054
BayesDel_addAF	Benign	-0.86	T
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.0030
DANN	Benign	0.44
DEOGEN2	Benign	0.069	T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.0068	N
LIST_S2	Benign	0.56	T
MetaRNN	Benign	0.0019	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	-0.77	N
PhyloP100		-2.1
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.37	N
REVEL	Benign	0.19
Sift	Benign	0.31	T
Sift4G	Benign	0.44	T
Polyphen		0.0	B
Vest4		0.015
MPC		0.15
ClinPred		0.034	T
GERP RS		-9.4
Varity_R		0.013
gMVP		0.12
Mutation Taster		=98/2	polymorphism (auto)

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: rs10935070; hg19: chr3-133341988; COSMIC: COSV53439574; COSMIC: COSV53439574;