8-143309468-G-A

Variant names:

• chr8-143309468-G-A
• rs112672243
• NM_052963.3:c.1779C>T

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4 BP6_Very_Strong BS1 BS2

The NM_052963.3(TOP1MT):​c.1779C>T​(p.Ala593Ala) variant causes a synonymous change. The variant allele was found at a frequency of 0.00257 in 1,613,924 control chromosomes in the GnomAD database, including 75 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (35 hom., cov: 33)
  • Exomes 𝑓: 0.0017 (40 hom.)
• Consequence: TOP1MT NM_052963.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.85
• Publications: 3 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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.19).
• BP6: Variant 8-143309468-G-A is Benign according to our data. Variant chr8-143309468-G-A is described in ClinVar as Benign. ClinVar VariationId is 1633361.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0109 (1661/152306) while in subpopulation AFR AF = 0.036 (1497/41550). AF 95% confidence interval is 0.0345. There are 35 homozygotes in GnomAd4. There are 791 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 35 AR gene

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.1779C>T	p.Ala593Ala	synonymous	Exon 14 of 14	NP_443195.1	Q969P6-1
	TOP1MT	NM_001258446.1		c.1485C>T	p.Ala495Ala	synonymous	Exon 15 of 15	NP_001245375.1	Q969P6-2
	TOP1MT	NM_001258447.1		c.1485C>T	p.Ala495Ala	synonymous	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.1779C>T	p.Ala593Ala	synonymous	Exon 14 of 14	ENSP00000328835.3	Q969P6-1
	TOP1MT	ENST00000969804.1		c.1869C>T	p.Ala623Ala	synonymous	Exon 14 of 14	ENSP00000639863.1
	TOP1MT	ENST00000870174.1		c.1824C>T	p.Ala608Ala	synonymous	Exon 14 of 14	ENSP00000540233.1

Frequencies

GnomAD3 genomes AF: 0.0108 AC: 1647 AN: 152188 Hom.: 34 Cov.: 33

Gnomad AFR AF: 0.0358

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00360

Gnomad ASJ AF: 0.0130

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.000573

Gnomad OTH AF: 0.00908

GnomAD2 exomes AF: 0.00340 AC: 853 AN: 251162 AF XY: 0.00271

Gnomad AFR exome AF: 0.0353

Gnomad AMR exome AF: 0.00226

Gnomad ASJ exome AF: 0.0129

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000492

Gnomad OTH exome AF: 0.00212

GnomAD4 exome AF: 0.00170 AC: 2492 AN: 1461618 Hom.: 40 Cov.: 30 AF XY: 0.00154 AC XY: 1119 AN XY: 727132

African (AFR) AF: 0.0381 AC: 1276 AN: 33480

American (AMR) AF: 0.00248 AC: 111 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0131 AC: 343 AN: 26132

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

South Asian (SAS) AF: 0.000116 AC: 10 AN: 86258

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53160

Middle Eastern (MID) AF: 0.00867 AC: 50 AN: 5768

European-Non Finnish (NFE) AF: 0.000406 AC: 452 AN: 1112004

Other (OTH) AF: 0.00412 AC: 249 AN: 60394

GnomAD4 genome AF: 0.0109 AC: 1661 AN: 152306 Hom.: 35 Cov.: 33 AF XY: 0.0106 AC XY: 791 AN XY: 74464

African (AFR) AF: 0.0360 AC: 1497 AN: 41550

American (AMR) AF: 0.00360 AC: 55 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0130 AC: 45 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.000573 AC: 39 AN: 68030

Other (OTH) AF: 0.00899 AC: 19 AN: 2114

Alfa AF: 0.00646 Hom.: 11

Bravo AF: 0.0119

Asia WGS AF: 0.00346 AC: 12 AN: 3478

EpiCase AF: 0.000927

EpiControl AF: 0.000711

ClinVar

ClinVar submissions

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	-0.44
CADD	Benign	1.5
DANN	Benign	0.69
PhyloP100		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=99/1	polymorphism

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: rs112672243; hg19: chr8-144391638;