chr8-143309558-A-G

Variant names:

• chr8-143309558-A-G
• rs7386475
• NM_052963.3:c.1704-15T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_052963.3(TOP1MT):​c.1704-15T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.556 in 1,612,382 control chromosomes in the GnomAD database, including 256,204 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.50 (20828 hom., cov: 32)
  • Exomes 𝑓: 0.56 (235376 hom.)
• Consequence: TOP1MT NM_052963.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.92
• Publications: 11 publications found

Genes affected

TOP1MT (HGNC:29787): (DNA topoisomerase I mitochondrial) This gene encodes a mitochondrial DNA topoisomerase that plays a role in the modification of DNA topology. The encoded protein is a type IB topoisomerase and catalyzes the transient breaking and rejoining of DNA to relieve tension and DNA supercoiling generated in the mitochondrial genome during replication and transcription. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, May 2012]

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 8-143309558-A-G is Benign according to our data. Variant chr8-143309558-A-G is described in ClinVar as Benign. ClinVar VariationId is 1599764.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.774 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_052963.3. 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
	TOP1MT	NM_052963.3	MANE Select	c.1704-15T>C		intron	N/A	NP_443195.1	Q969P6-1
	TOP1MT	NM_001258446.1		c.1410-15T>C		intron	N/A	NP_001245375.1	Q969P6-2
	TOP1MT	NM_001258447.1		c.1410-15T>C		intron	N/A	NP_001245376.1	Q969P6-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TOP1MT	ENST00000329245.9	TSL:1 MANE Select	c.1704-15T>C		intron	N/A	ENSP00000328835.3	Q969P6-1
	TOP1MT	ENST00000870174.1		c.1734T>C	p.Asp578Asp	synonymous	Exon 14 of 14	ENSP00000540233.1
	TOP1MT	ENST00000969804.1		c.1794-15T>C		intron	N/A	ENSP00000639863.1

Frequencies

GnomAD3 genomes AF: 0.503 AC: 76469 AN: 151930 Hom.: 20811 Cov.: 32

Gnomad AFR AF: 0.293

Gnomad AMI AF: 0.563

Gnomad AMR AF: 0.642

Gnomad ASJ AF: 0.518

Gnomad EAS AF: 0.794

Gnomad SAS AF: 0.709

Gnomad FIN AF: 0.593

Gnomad MID AF: 0.395

Gnomad NFE AF: 0.548

Gnomad OTH AF: 0.505

GnomAD2 exomes AF: 0.594 AC: 148563 AN: 249972 AF XY: 0.596

Gnomad AFR exome AF: 0.287

Gnomad AMR exome AF: 0.739

Gnomad ASJ exome AF: 0.508

Gnomad EAS exome AF: 0.803

Gnomad FIN exome AF: 0.599

Gnomad NFE exome AF: 0.539

Gnomad OTH exome AF: 0.560

GnomAD4 exome AF: 0.561 AC: 819400 AN: 1460334 Hom.: 235376 Cov.: 60 AF XY: 0.565 AC XY: 410188 AN XY: 726442

African (AFR) AF: 0.277 AC: 9267 AN: 33470

American (AMR) AF: 0.726 AC: 32449 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.506 AC: 13215 AN: 26132

East Asian (EAS) AF: 0.806 AC: 31995 AN: 39688

South Asian (SAS) AF: 0.699 AC: 60246 AN: 86248

European-Finnish (FIN) AF: 0.599 AC: 31318 AN: 52324

Middle Eastern (MID) AF: 0.445 AC: 2567 AN: 5766

European-Non Finnish (NFE) AF: 0.544 AC: 605043 AN: 1111638

Other (OTH) AF: 0.552 AC: 33300 AN: 60364

GnomAD4 genome AF: 0.503 AC: 76517 AN: 152048 Hom.: 20828 Cov.: 32 AF XY: 0.513 AC XY: 38152 AN XY: 74318

African (AFR) AF: 0.293 AC: 12158 AN: 41486

American (AMR) AF: 0.643 AC: 9811 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.518 AC: 1796 AN: 3470

East Asian (EAS) AF: 0.795 AC: 4084 AN: 5140

South Asian (SAS) AF: 0.709 AC: 3418 AN: 4822

European-Finnish (FIN) AF: 0.593 AC: 6275 AN: 10578

Middle Eastern (MID) AF: 0.397 AC: 116 AN: 292

European-Non Finnish (NFE) AF: 0.548 AC: 37274 AN: 67970

Other (OTH) AF: 0.508 AC: 1073 AN: 2112

Alfa AF: 0.459 Hom.: 2540

Bravo AF: 0.495

Asia WGS AF: 0.714 AC: 2484 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.90
DANN	Benign	0.44
PhyloP100		-1.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	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: rs7386475; hg19: chr8-144391728; COSMIC: COSV100239508;