8-143321315-G-C

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BA1

The NM_052963.3(TOP1MT):c.1032C>G(p.Arg344=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.285 in 1,609,856 control chromosomes in the GnomAD database, including 69,488 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.32 (8709 hom., cov: 34)
  • Exomes 𝑓: 0.28 (60779 hom.)
• Consequence: TOP1MT NM_052963.3 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -3.49

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

Verdict is Benign. Variant got -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 8-143321315-G-C is Benign according to our data. Variant chr8-143321315-G-C is described in ClinVar as [Benign]. Clinvar id is 1645543.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-3.49 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.464 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TOP1MT	NM_052963.3	c.1032C>G	p.Arg344=	synonymous_variant	8/14	ENST00000329245.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TOP1MT	ENST00000329245.9	c.1032C>G	p.Arg344=	synonymous_variant	8/14	1	NM_052963.3	P1

Frequencies

GnomAD3 genomes AF: 0.322 AC: 48976 AN: 152008 Hom.: 8702 Cov.: 34

Gnomad AFR AF: 0.470

Gnomad AMI AF: 0.312

Gnomad AMR AF: 0.225

Gnomad ASJ AF: 0.263

Gnomad EAS AF: 0.0743

Gnomad SAS AF: 0.209

Gnomad FIN AF: 0.283

Gnomad MID AF: 0.358

Gnomad NFE AF: 0.290

Gnomad OTH AF: 0.326

GnomAD3 exomes AF: 0.259 AC: 64224 AN: 248048 Hom.: 9613 AF XY: 0.259 AC XY: 34773 AN XY: 134310

Gnomad AFR exome AF: 0.471

Gnomad AMR exome AF: 0.168

Gnomad ASJ exome AF: 0.274

Gnomad EAS exome AF: 0.0664

Gnomad SAS exome AF: 0.216

Gnomad FIN exome AF: 0.276

Gnomad NFE exome AF: 0.294

Gnomad OTH exome AF: 0.274

GnomAD4 exome AF: 0.281 AC: 410128 AN: 1457732 Hom.: 60779 Cov.: 39 AF XY: 0.280 AC XY: 202939 AN XY: 724932

Gnomad4 AFR exome AF: 0.482

Gnomad4 AMR exome AF: 0.177

Gnomad4 ASJ exome AF: 0.274

Gnomad4 EAS exome AF: 0.0660

Gnomad4 SAS exome AF: 0.220

Gnomad4 FIN exome AF: 0.281

Gnomad4 NFE exome AF: 0.292

Gnomad4 OTH exome AF: 0.285

GnomAD4 genome AF: 0.322 AC: 49003 AN: 152124 Hom.: 8709 Cov.: 34 AF XY: 0.316 AC XY: 23504 AN XY: 74382

Gnomad4 AFR AF: 0.470

Gnomad4 AMR AF: 0.224

Gnomad4 ASJ AF: 0.263

Gnomad4 EAS AF: 0.0740

Gnomad4 SAS AF: 0.209

Gnomad4 FIN AF: 0.283

Gnomad4 NFE AF: 0.290

Gnomad4 OTH AF: 0.324

Alfa AF: 0.248 Hom.: 1585

Bravo AF: 0.324

EpiCase AF: 0.297

EpiControl AF: 0.290

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
Cadd	Benign	0.59
Dann	Benign	0.64

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs11544482; hg19: chr8-144403485; COSMIC: COSV61318065; COSMIC: COSV61318065;