rs2293925

Positions:

• chr8-143310198-G-A
• chr8-143310198-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_052963.3(TOP1MT):​c.1573C>T​(p.Arg525Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.449 in 1,579,896 control chromosomes in the GnomAD database, including 169,713 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.38 (13454 hom., cov: 33)
  • Exomes 𝑓: 0.46 (156259 hom.)
• Consequence: TOP1MT NM_052963.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.176

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=4.9609944E-6).
• BP6: Variant 8-143310198-G-A is Benign according to our data. Variant chr8-143310198-G-A is described in ClinVar as [Benign]. Clinvar id is 1645532.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.664 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TOP1MT	NM_052963.3	c.1573C>T	p.Arg525Trp	missense_variant	13/14	ENST00000329245.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TOP1MT	ENST00000329245.9	c.1573C>T	p.Arg525Trp	missense_variant	13/14	1	NM_052963.3	P1

Frequencies

GnomAD3 genomes AF: 0.376 AC: 57154 AN: 151956 Hom.: 13436 Cov.: 33

Gnomad AFR AF: 0.0975

Gnomad AMI AF: 0.467

Gnomad AMR AF: 0.556

Gnomad ASJ AF: 0.346

Gnomad EAS AF: 0.683

Gnomad SAS AF: 0.636

Gnomad FIN AF: 0.523

Gnomad MID AF: 0.301

Gnomad NFE AF: 0.441

Gnomad OTH AF: 0.387

GnomAD3 exomes AF: 0.505 AC: 107399 AN: 212494 Hom.: 29468 AF XY: 0.511 AC XY: 58990 AN XY: 115490

Gnomad AFR exome AF: 0.0907

Gnomad AMR exome AF: 0.682

Gnomad ASJ exome AF: 0.362

Gnomad EAS exome AF: 0.708

Gnomad SAS exome AF: 0.637

Gnomad FIN exome AF: 0.537

Gnomad NFE exome AF: 0.446

Gnomad OTH exome AF: 0.471

GnomAD4 exome AF: 0.457 AC: 652480 AN: 1427822 Hom.: 156259 Cov.: 41 AF XY: 0.462 AC XY: 326913 AN XY: 707740

Gnomad4 AFR exome AF: 0.0806

Gnomad4 AMR exome AF: 0.661

Gnomad4 ASJ exome AF: 0.343

Gnomad4 EAS exome AF: 0.704

Gnomad4 SAS exome AF: 0.627

Gnomad4 FIN exome AF: 0.528

Gnomad4 NFE exome AF: 0.440

Gnomad4 OTH exome AF: 0.440

GnomAD4 genome AF: 0.376 AC: 57188 AN: 152074 Hom.: 13454 Cov.: 33 AF XY: 0.389 AC XY: 28937 AN XY: 74340

Gnomad4 AFR AF: 0.0973

Gnomad4 AMR AF: 0.557

Gnomad4 ASJ AF: 0.346

Gnomad4 EAS AF: 0.683

Gnomad4 SAS AF: 0.635

Gnomad4 FIN AF: 0.523

Gnomad4 NFE AF: 0.441

Gnomad4 OTH AF: 0.390

Alfa AF: 0.429 Hom.: 13535

Bravo AF: 0.364

TwinsUK AF: 0.430 AC: 1593

ALSPAC AF: 0.450 AC: 1734

ESP6500AA AF: 0.0987 AC: 434

ESP6500EA AF: 0.441 AC: 3794

ExAC AF: 0.470 AC: 56544

Asia WGS AF: 0.610 AC: 2123 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.35	T;.;.;.
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.48
FATHMM_MKL	Benign	0.28	N
LIST_S2	Uncertain	0.89	D;.;.;D
MetaRNN	Benign	0.0000050	T;T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Uncertain	2.3	M;.;.;.
MutationTaster	Benign	1.0	P;P;P;P
PrimateAI	Benign	0.36	T
PROVEAN	Uncertain	-4.3	D;D;D;D
REVEL	Benign	0.14
Sift	Uncertain	0.019	D;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;D
Polyphen		0.99	D;.;.;.
Vest4		0.12
MPC		0.19
ClinPred		0.043	T
GERP RS		-3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3
Varity_R		0.12
gMVP		0.24

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: rs2293925; hg19: chr8-144392368; COSMIC: COSV61319143;