rs11544484

Variant names:

• chr8-143324535-C-T
• rs11544484
• NM_052963.3:c.766G>A

Your query was ambiguous. Multiple possible variants found:

• chr8-143324535-C-T
• chr8-143324535-C-A
• chr8-143324535-C-G

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.766G>A​(p.Val256Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.286 in 1,613,628 control chromosomes in the GnomAD database, including 70,245 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 (★★).

• Frequency:
  • Genomes: 𝑓 0.33 (9016 hom., cov: 33)
  • Exomes 𝑓: 0.28 (61229 hom.)
• Consequence: TOP1MT NM_052963.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.44
• Publications: 43 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 (MetaRNN=7.775426E-4).
• BP6: Variant 8-143324535-C-T is Benign according to our data. Variant chr8-143324535-C-T is described in ClinVar as Benign. ClinVar VariationId is 1251430.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.479 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.766G>A	p.Val256Ile	missense	Exon 6 of 14	NP_443195.1	Q969P6-1
	TOP1MT	NM_001258446.1		c.472G>A	p.Val158Ile	missense	Exon 7 of 15	NP_001245375.1	Q969P6-2
	TOP1MT	NM_001258447.1		c.472G>A	p.Val158Ile	missense	Exon 6 of 14	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.766G>A	p.Val256Ile	missense	Exon 6 of 14	ENSP00000328835.3	Q969P6-1
	TOP1MT	ENST00000969804.1		c.766G>A	p.Val256Ile	missense	Exon 6 of 14	ENSP00000639863.1
	TOP1MT	ENST00000870174.1		c.766G>A	p.Val256Ile	missense	Exon 6 of 14	ENSP00000540233.1

Frequencies

GnomAD3 genomes AF: 0.327 AC: 49624 AN: 151970 Hom.: 9002 Cov.: 33

Gnomad AFR AF: 0.485

Gnomad AMI AF: 0.314

Gnomad AMR AF: 0.227

Gnomad ASJ AF: 0.262

Gnomad EAS AF: 0.0744

Gnomad SAS AF: 0.209

Gnomad FIN AF: 0.289

Gnomad MID AF: 0.354

Gnomad NFE AF: 0.289

Gnomad OTH AF: 0.330

GnomAD2 exomes AF: 0.263 AC: 65997 AN: 251280 AF XY: 0.262

Gnomad AFR exome AF: 0.488

Gnomad AMR exome AF: 0.171

Gnomad ASJ exome AF: 0.274

Gnomad EAS exome AF: 0.0669

Gnomad FIN exome AF: 0.285

Gnomad NFE exome AF: 0.296

Gnomad OTH exome AF: 0.277

GnomAD4 exome AF: 0.282 AC: 412146 AN: 1461540 Hom.: 61229 Cov.: 46 AF XY: 0.281 AC XY: 204049 AN XY: 727084

African (AFR) AF: 0.497 AC: 16634 AN: 33478

American (AMR) AF: 0.179 AC: 7997 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.274 AC: 7154 AN: 26136

East Asian (EAS) AF: 0.0670 AC: 2660 AN: 39698

South Asian (SAS) AF: 0.221 AC: 19086 AN: 86258

European-Finnish (FIN) AF: 0.288 AC: 15330 AN: 53142

Middle Eastern (MID) AF: 0.341 AC: 1968 AN: 5766

European-Non Finnish (NFE) AF: 0.291 AC: 324029 AN: 1111958

Other (OTH) AF: 0.286 AC: 17288 AN: 60386

GnomAD4 genome AF: 0.327 AC: 49665 AN: 152088 Hom.: 9016 Cov.: 33 AF XY: 0.321 AC XY: 23849 AN XY: 74350

African (AFR) AF: 0.485 AC: 20103 AN: 41466

American (AMR) AF: 0.226 AC: 3460 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.262 AC: 911 AN: 3472

East Asian (EAS) AF: 0.0742 AC: 384 AN: 5178

South Asian (SAS) AF: 0.210 AC: 1011 AN: 4822

European-Finnish (FIN) AF: 0.289 AC: 3063 AN: 10594

Middle Eastern (MID) AF: 0.347 AC: 102 AN: 294

European-Non Finnish (NFE) AF: 0.289 AC: 19655 AN: 67966

Other (OTH) AF: 0.328 AC: 690 AN: 2104

Alfa AF: 0.299 Hom.: 22727

Bravo AF: 0.329

TwinsUK AF: 0.293 AC: 1088

ALSPAC AF: 0.292 AC: 1124

ESP6500AA AF: 0.495 AC: 2179

ESP6500EA AF: 0.282 AC: 2426

ExAC AF: 0.270 AC: 32817

Asia WGS AF: 0.176 AC: 612 AN: 3478

EpiCase AF: 0.297

EpiControl AF: 0.290

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	0.87
DANN	Benign	0.37
DEOGEN2	Benign	0.057	T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.24	N
LIST_S2	Benign	0.62	T
MetaRNN	Benign	0.00078	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.91	N
PhyloP100		1.4
PrimateAI	Benign	0.39	T
PROVEAN	Benign	0.35	N
REVEL	Benign	0.071
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.010	B
Vest4		0.032
MPC		0.16
ClinPred		0.0021	T
GERP RS		-7.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.011
gMVP		0.085
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: rs11544484; hg19: chr8-144406705; COSMIC: COSV61316152; COSMIC: COSV61316152;