chr8-143331246-G-A

Variant names:

• chr8-143331246-G-A
• rs2450772
• NM_052963.3:c.216C>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.216C>T​(p.Asp72Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.123 in 1,609,386 control chromosomes in the GnomAD database, including 15,684 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.19 (4186 hom., cov: 33)
  • Exomes 𝑓: 0.12 (11498 hom.)
• Consequence: TOP1MT NM_052963.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.16
• Publications: 20 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=-0.91).
• BP6: Variant 8-143331246-G-A is Benign according to our data. Variant chr8-143331246-G-A is described in ClinVar as Benign. ClinVar VariationId is 1598715.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.16 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.403 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.216C>T	p.Asp72Asp	synonymous	Exon 2 of 14	NP_443195.1
	TOP1MT	NM_001258446.1		c.-79C>T		5_prime_UTR_premature_start_codon_gain	Exon 3 of 15	NP_001245375.1
	TOP1MT	NM_001258447.1		c.-79C>T		5_prime_UTR_premature_start_codon_gain	Exon 2 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.216C>T	p.Asp72Asp	synonymous	Exon 2 of 14	ENSP00000328835.3
	TOP1MT	ENST00000519148.5	TSL:2	c.-79C>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 14	ENSP00000429169.1
	TOP1MT	ENST00000521193.5	TSL:2	c.-79C>T		5_prime_UTR_premature_start_codon_gain	Exon 3 of 15	ENSP00000428369.1

Frequencies

GnomAD3 genomes AF: 0.192 AC: 29178 AN: 152024 Hom.: 4185 Cov.: 33

Gnomad AFR AF: 0.409

Gnomad AMI AF: 0.0308

Gnomad AMR AF: 0.112

Gnomad ASJ AF: 0.185

Gnomad EAS AF: 0.0734

Gnomad SAS AF: 0.0945

Gnomad FIN AF: 0.0948

Gnomad MID AF: 0.0949

Gnomad NFE AF: 0.112

Gnomad OTH AF: 0.183

GnomAD2 exomes AF: 0.121 AC: 30274 AN: 250516 AF XY: 0.115

Gnomad AFR exome AF: 0.415

Gnomad AMR exome AF: 0.0755

Gnomad ASJ exome AF: 0.175

Gnomad EAS exome AF: 0.0682

Gnomad FIN exome AF: 0.101

Gnomad NFE exome AF: 0.108

Gnomad OTH exome AF: 0.115

GnomAD4 exome AF: 0.115 AC: 168208 AN: 1457244 Hom.: 11498 Cov.: 31 AF XY: 0.114 AC XY: 82451 AN XY: 724274

African (AFR) AF: 0.408 AC: 13634 AN: 33422

American (AMR) AF: 0.0823 AC: 3669 AN: 44568

Ashkenazi Jewish (ASJ) AF: 0.180 AC: 4678 AN: 26036

East Asian (EAS) AF: 0.0757 AC: 2996 AN: 39588

South Asian (SAS) AF: 0.0913 AC: 7853 AN: 86042

European-Finnish (FIN) AF: 0.100 AC: 5348 AN: 53286

Middle Eastern (MID) AF: 0.0934 AC: 537 AN: 5752

European-Non Finnish (NFE) AF: 0.110 AC: 121593 AN: 1108440

Other (OTH) AF: 0.131 AC: 7900 AN: 60110

GnomAD4 genome AF: 0.192 AC: 29190 AN: 152142 Hom.: 4186 Cov.: 33 AF XY: 0.185 AC XY: 13755 AN XY: 74390

African (AFR) AF: 0.408 AC: 16930 AN: 41462

American (AMR) AF: 0.112 AC: 1707 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.185 AC: 642 AN: 3468

East Asian (EAS) AF: 0.0734 AC: 380 AN: 5176

South Asian (SAS) AF: 0.0938 AC: 453 AN: 4830

European-Finnish (FIN) AF: 0.0948 AC: 1006 AN: 10614

Middle Eastern (MID) AF: 0.0884 AC: 26 AN: 294

European-Non Finnish (NFE) AF: 0.112 AC: 7635 AN: 67974

Other (OTH) AF: 0.181 AC: 383 AN: 2114

Alfa AF: 0.136 Hom.: 8137

Bravo AF: 0.201

Asia WGS AF: 0.107 AC: 372 AN: 3478

EpiCase AF: 0.111

EpiControl AF: 0.110

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	-0.91
CADD	Benign	2.8
DANN	Benign	0.49
PhyloP100		-1.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=300/0	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: rs2450772; hg19: chr8-144413416; COSMIC: COSV61317003; COSMIC: COSV61317003;