rs144859839

Variant names:

• chr8-143309443-A-T
• rs144859839
• NM_052963.3:c.1804T>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM4

The NM_052963.3(TOP1MT):​c.1804T>A​(p.Ter602Lysext*?) variant causes a stop lost change. The variant allele was found at a frequency of 0.0000459 in 1,613,496 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000044 (0 hom.)
• Consequence: TOP1MT NM_052963.3 stop_lost
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.25
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

• PM4: Stoplost variant in NM_052963.3 Downstream stopcodon found after 84 codons.

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.1804T>A	p.Ter602Lysext*?	stop_lost	Exon 14 of 14	NP_443195.1	Q969P6-1
	TOP1MT	NM_001258446.1		c.1510T>A	p.Ter504Lysext*?	stop_lost	Exon 15 of 15	NP_001245375.1	Q969P6-2
	TOP1MT	NM_001258447.1		c.1510T>A	p.Ter504Lysext*?	stop_lost	Exon 14 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.1804T>A	p.Ter602Lysext*?	stop_lost	Exon 14 of 14	ENSP00000328835.3	Q969P6-1
	TOP1MT	ENST00000969804.1		c.1894T>A	p.Ter632Lysext*?	stop_lost	Exon 14 of 14	ENSP00000639863.1
	TOP1MT	ENST00000870174.1		c.1849T>A	p.Ter617Lysext*?	stop_lost	Exon 14 of 14	ENSP00000540233.1

Frequencies

GnomAD3 genomes AF: 0.0000657 AC: 10 AN: 152236 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000518 AC: 13 AN: 250812 AF XY: 0.0000737

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000795

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000438 AC: 64 AN: 1461260 Hom.: 0 Cov.: 29 AF XY: 0.0000385 AC XY: 28 AN XY: 726974

African (AFR) AF: 0.0000299 AC: 1 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.000880 AC: 23 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52880

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5768

European-Non Finnish (NFE) AF: 0.0000216 AC: 24 AN: 1111946

Other (OTH) AF: 0.000149 AC: 9 AN: 60390

GnomAD4 genome AF: 0.0000657 AC: 10 AN: 152236 Hom.: 0 Cov.: 33 AF XY: 0.0000672 AC XY: 5 AN XY: 74368

African (AFR) AF: 0.00 AC: 0 AN: 41462

American (AMR) AF: 0.00 AC: 0 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000136 Hom.: 0

Bravo AF: 0.0000491

ExAC AF: 0.0000412 AC: 5

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	11
DANN	Benign	0.54
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Uncertain	0.93	D
PhyloP100		6.2
Vest4		0.021
ClinPred		0.67	D
GERP RS		3.9
Mutation Taster		=60/140	disease causing

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: rs144859839; hg19: chr8-144391613;