8-143309496-T-G

Position:

• chr8-143309496-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_052963.3(TOP1MT):​c.1751A>C​(p.Gln584Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000342 in 1,461,716 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: TOP1MT NM_052963.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.18

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.812

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TOP1MT	NM_052963.3	c.1751A>C	p.Gln584Pro	missense_variant	14/14	ENST00000329245.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TOP1MT	ENST00000329245.9	c.1751A>C	p.Gln584Pro	missense_variant	14/14	1	NM_052963.3	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461716 Hom.: 0 Cov.: 29 AF XY: 0.00000550 AC XY: 4 AN XY: 727180

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 10, 2023

The c.1751A>C (p.Q584P) alteration is located in exon 14 (coding exon 14) of the TOP1MT gene. This alteration results from a A to C substitution at nucleotide position 1751, causing the glutamine (Q) at amino acid position 584 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Uncertain	0.020	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.55	D;.;.;.
Eigen	Uncertain	0.38
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Pathogenic	0.99	D;.;.;D
M_CAP	Benign	0.040	D
MetaRNN	Pathogenic	0.81	D;D;D;D
MetaSVM	Benign	-0.48	T
MutationAssessor	Uncertain	2.9	M;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Benign	0.46	T
PROVEAN	Pathogenic	-4.9	D;D;D;D
REVEL	Benign	0.28
Sift	Uncertain	0.027	D;D;D;D
Sift4G	Uncertain	0.017	D;D;D;D
Polyphen		1.0	D;.;.;.
Vest4		0.75
MutPred		0.41		Gain of glycosylation at Q584 (P = 0.0323);.;.;.;
MVP		0.66
MPC		0.82
ClinPred		0.99	D
GERP RS		3.1
Varity_R		0.86
gMVP		0.72

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr8-144391666;