8-143321315-G-C

Variant names:

• chr8-143321315-G-C
• rs11544482
• NM_052963.3:c.1032C>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_052963.3(TOP1MT):​c.1032C>G​(p.Arg344Arg) 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, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -3.49
• Publications: 13 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 -21 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 VariationId is 1645543.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TOP1MT	NM_052963.3	MANE Select	c.1032C>G	p.Arg344Arg	synonymous	Exon 8 of 14	NP_443195.1
	TOP1MT	NM_001258446.1		c.738C>G	p.Arg246Arg	synonymous	Exon 9 of 15	NP_001245375.1
	TOP1MT	NM_001258447.1		c.738C>G	p.Arg246Arg	synonymous	Exon 8 of 14	NP_001245376.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TOP1MT	ENST00000329245.9	TSL:1 MANE Select	c.1032C>G	p.Arg344Arg	synonymous	Exon 8 of 14	ENSP00000328835.3
	TOP1MT	ENST00000969804.1		c.1032C>G	p.Arg344Arg	synonymous	Exon 8 of 14	ENSP00000639863.1
	TOP1MT	ENST00000870174.1		c.1032C>G	p.Arg344Arg	synonymous	Exon 8 of 14	ENSP00000540233.1

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

GnomAD2 exomes AF: 0.259 AC: 64224 AN: 248048 AF XY: 0.259

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 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

African (AFR) AF: 0.482 AC: 16086 AN: 33346

American (AMR) AF: 0.177 AC: 7840 AN: 44414

Ashkenazi Jewish (ASJ) AF: 0.274 AC: 7130 AN: 26006

East Asian (EAS) AF: 0.0660 AC: 2614 AN: 39624

South Asian (SAS) AF: 0.220 AC: 18950 AN: 85976

European-Finnish (FIN) AF: 0.281 AC: 14837 AN: 52838

Middle Eastern (MID) AF: 0.345 AC: 1983 AN: 5750

European-Non Finnish (NFE) AF: 0.292 AC: 323528 AN: 1109568

Other (OTH) AF: 0.285 AC: 17160 AN: 60210

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

African (AFR) AF: 0.470 AC: 19476 AN: 41444

American (AMR) AF: 0.224 AC: 3431 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.263 AC: 913 AN: 3470

East Asian (EAS) AF: 0.0740 AC: 384 AN: 5186

South Asian (SAS) AF: 0.209 AC: 1011 AN: 4828

European-Finnish (FIN) AF: 0.283 AC: 2995 AN: 10596

Middle Eastern (MID) AF: 0.350 AC: 103 AN: 294

European-Non Finnish (NFE) AF: 0.290 AC: 19721 AN: 67982

Other (OTH) AF: 0.324 AC: 685 AN: 2112

Alfa AF: 0.248 Hom.: 1585

Bravo AF: 0.324

EpiCase AF: 0.297

EpiControl AF: 0.290

ClinVar

ClinVar submissions as Germline

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	0.59
DANN	Benign	0.64
PhyloP100		-3.5
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

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