8-143324535-C-G

Variant names:

• chr8-143324535-C-G
• rs11544484
• NM_052963.3:c.766G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_052963.3(TOP1MT):​c.766G>C​(p.Val256Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 15/22 in silico tools predict a benign 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. V256I) has been classified as Benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TOP1MT NM_052963.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.44
• 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TOP1MT	NM_052963.3	MANE Select	c.766G>C	p.Val256Leu	missense	Exon 6 of 14	NP_443195.1
	TOP1MT	NM_001258446.1		c.472G>C	p.Val158Leu	missense	Exon 7 of 15	NP_001245375.1
	TOP1MT	NM_001258447.1		c.472G>C	p.Val158Leu	missense	Exon 6 of 14	NP_001245376.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TOP1MT	ENST00000329245.9	TSL:1 MANE Select	c.766G>C	p.Val256Leu	missense	Exon 6 of 14	ENSP00000328835.3
	TOP1MT	ENST00000969804.1		c.766G>C	p.Val256Leu	missense	Exon 6 of 14	ENSP00000639863.1
	TOP1MT	ENST00000870174.1		c.766G>C	p.Val256Leu	missense	Exon 6 of 14	ENSP00000540233.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 46

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.088	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	13
DANN	Benign	0.85
DEOGEN2	Benign	0.098	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.71	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.0074	T
MetaRNN	Uncertain	0.57	D
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	2.0	M
PhyloP100		1.4
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.23
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0040	D
Polyphen		0.25	B
Vest4		0.23
MutPred		0.78		Loss of MoRF binding (P = 0.1062)
MVP		0.39
MPC		0.35
ClinPred		0.40	T
GERP RS		-7.1
Varity_R		0.26
gMVP		0.18
Mutation Taster		=98/2	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: rs11544484; hg19: chr8-144406705;