8-143310174-G-C

Variant names:

• chr8-143310174-G-C
• rs149953316
• NM_052963.3:c.1597C>G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_052963.3(TOP1MT):​c.1597C>G​(p.Gln533Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00000657 in 152,202 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: TOP1MT NM_052963.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.83

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

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27572304).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TOP1MT	NM_052963.3	c.1597C>G	p.Gln533Glu	missense_variant	Exon 13 of 14	ENST00000329245.9	NP_443195.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TOP1MT	ENST00000329245.9	c.1597C>G	p.Gln533Glu	missense_variant	Exon 13 of 14	1	NM_052963.3	ENSP00000328835.3

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152202 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 37

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152202 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74368

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.011	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.30	T;.;.;.
Eigen	Benign	0.022
Eigen_PC	Benign	-0.00037
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.94	D;.;.;D
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.28	T;T;T;T
MetaSVM	Benign	-0.35	T
MutationAssessor	Uncertain	2.9	M;.;.;.
PrimateAI	Benign	0.39	T
PROVEAN	Uncertain	-2.6	D;D;D;D
REVEL	Benign	0.22
Sift	Uncertain	0.0060	D;D;D;D
Sift4G	Uncertain	0.010	D;D;D;D
Polyphen		0.032	B;.;.;.
Vest4		0.37
MutPred		0.23		Loss of MoRF binding (P = 0.0457);.;.;.;
MVP		0.78
MPC		0.38
ClinPred		0.78	D
GERP RS		4.0
Varity_R		0.41
gMVP		0.17

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

Publications

LitVar

Other links and lift over

dbSNP: rs149953316; hg19: chr8-144392344;