8-143315778-A-C

Variant names:

• chr8-143315778-A-C
• rs1390291631
• NM_052963.3:c.1502T>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_052963.3(TOP1MT):​c.1502T>G​(p.Leu501Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L501P) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TOP1MT NM_052963.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.78
• 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.764

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TOP1MT	NM_052963.3	c.1502T>G	p.Leu501Arg	missense_variant	Exon 12 of 14	ENST00000329245.9	NP_443195.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TOP1MT	ENST00000329245.9	c.1502T>G	p.Leu501Arg	missense_variant	Exon 12 of 14	1	NM_052963.3	ENSP00000328835.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Uncertain	0.083	D
BayesDel_noAF	Benign	-0.12
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.29	T;.;.;.
Eigen	Uncertain	0.35
Eigen_PC	Benign	0.14
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.73	T;.;.;T
M_CAP	Benign	0.054	D
MetaRNN	Pathogenic	0.76	D;D;D;D
MetaSVM	Uncertain	-0.28	T
MutationAssessor	Uncertain	2.8	M;.;.;.
PhyloP100		5.8
PrimateAI	Uncertain	0.60	T
PROVEAN	Pathogenic	-4.5	D;D;D;D
REVEL	Uncertain	0.31
Sift	Uncertain	0.027	D;D;D;D
Sift4G	Benign	0.061	T;T;T;T
Polyphen		1.0	D;.;.;.
Vest4		0.75
MutPred		0.52		Gain of methylation at L501 (P = 0.0503);.;.;.;
MVP		0.66
MPC		0.90
ClinPred		0.98	D
GERP RS		3.6
PromoterAI		0.011	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.53
gMVP		0.50
Mutation Taster		=75/25	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: rs1390291631; hg19: chr8-144397948;