rs61631623

Variant names:

• chr8-143321279-G-A
• rs61631623
• NM_052963.3:c.1068C>T

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.1068C>T​(p.Gly356Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.105 in 1,612,194 control chromosomes in the GnomAD database, including 9,632 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1379 hom., cov: 33)
  • Exomes 𝑓: 0.10 (8253 hom.)
• Consequence: TOP1MT NM_052963.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.450
• Publications: 9 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=-0.81).
• BP6: Variant 8-143321279-G-A is Benign according to our data. Variant chr8-143321279-G-A is described in ClinVar as Benign. ClinVar VariationId is 1529061.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.45 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.191 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.1068C>T	p.Gly356Gly	synonymous	Exon 8 of 14	NP_443195.1
	TOP1MT	NM_001258446.1		c.774C>T	p.Gly258Gly	synonymous	Exon 9 of 15	NP_001245375.1
	TOP1MT	NM_001258447.1		c.774C>T	p.Gly258Gly	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.1068C>T	p.Gly356Gly	synonymous	Exon 8 of 14	ENSP00000328835.3
	TOP1MT	ENST00000519148.5	TSL:2	c.774C>T	p.Gly258Gly	synonymous	Exon 8 of 14	ENSP00000429169.1
	TOP1MT	ENST00000521193.5	TSL:2	c.774C>T	p.Gly258Gly	synonymous	Exon 9 of 15	ENSP00000428369.1

Frequencies

GnomAD3 genomes AF: 0.125 AC: 19062 AN: 152128 Hom.: 1381 Cov.: 33

Gnomad AFR AF: 0.195

Gnomad AMI AF: 0.0954

Gnomad AMR AF: 0.0847

Gnomad ASJ AF: 0.171

Gnomad EAS AF: 0.0749

Gnomad SAS AF: 0.0737

Gnomad FIN AF: 0.0708

Gnomad MID AF: 0.0981

Gnomad NFE AF: 0.106

Gnomad OTH AF: 0.119

GnomAD2 exomes AF: 0.0959 AC: 23873 AN: 249040 AF XY: 0.0939

Gnomad AFR exome AF: 0.198

Gnomad AMR exome AF: 0.0600

Gnomad ASJ exome AF: 0.160

Gnomad EAS exome AF: 0.0656

Gnomad FIN exome AF: 0.0715

Gnomad NFE exome AF: 0.102

Gnomad OTH exome AF: 0.0969

GnomAD4 exome AF: 0.103 AC: 150286 AN: 1459948 Hom.: 8253 Cov.: 33 AF XY: 0.102 AC XY: 73922 AN XY: 726238

African (AFR) AF: 0.197 AC: 6591 AN: 33416

American (AMR) AF: 0.0652 AC: 2908 AN: 44632

Ashkenazi Jewish (ASJ) AF: 0.164 AC: 4278 AN: 26078

East Asian (EAS) AF: 0.0805 AC: 3192 AN: 39654

South Asian (SAS) AF: 0.0731 AC: 6298 AN: 86164

European-Finnish (FIN) AF: 0.0712 AC: 3770 AN: 52964

Middle Eastern (MID) AF: 0.0823 AC: 474 AN: 5758

European-Non Finnish (NFE) AF: 0.105 AC: 116244 AN: 1110982

Other (OTH) AF: 0.108 AC: 6531 AN: 60300

GnomAD4 genome AF: 0.125 AC: 19077 AN: 152246 Hom.: 1379 Cov.: 33 AF XY: 0.123 AC XY: 9127 AN XY: 74452

African (AFR) AF: 0.195 AC: 8092 AN: 41526

American (AMR) AF: 0.0847 AC: 1296 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.171 AC: 594 AN: 3472

East Asian (EAS) AF: 0.0749 AC: 388 AN: 5182

South Asian (SAS) AF: 0.0737 AC: 356 AN: 4828

European-Finnish (FIN) AF: 0.0708 AC: 751 AN: 10614

Middle Eastern (MID) AF: 0.0918 AC: 27 AN: 294

European-Non Finnish (NFE) AF: 0.106 AC: 7238 AN: 68002

Other (OTH) AF: 0.117 AC: 248 AN: 2114

Alfa AF: 0.118 Hom.: 589

Bravo AF: 0.128

Asia WGS AF: 0.0920 AC: 320 AN: 3478

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	-0.81
CADD	Benign	1.4
DANN	Benign	0.56
PhyloP100		-0.45
Mutation Taster		=100/0	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: rs61631623; hg19: chr8-144403449; COSMIC: COSV61317937; COSMIC: COSV61317937;