chrM-9166-T-C

Position:

• chrM-9166-T-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BS2

Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Mitomap GenBank: 𝑓 0.0 (AC: 0)
• Consequence: ATP6 missense
• Scores: Apogee2 Uncertain 0.42
• Clinical Significance: Uncertain significance criteria provided, single submitter P:2 U:1 EXIT+more-/-bilateral-optic-neuropathy
• Conservation: PhyloP100: 5.95

Genes affected

ATP6 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very low frequency in mitomap database: 0.0
• BS2: High AC in GnomadMitoHomoplasmic at 4

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATP6	unassigned_transcript_4806	c.640T>C	p.Phe214Leu	missense_variant	1/1
COX3	unassigned_transcript_4807	c.-41T>C		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt

Frequencies

GnomAD4 exome Cov.: 0

We have no GnomAD4 genomes data on this position. Probably position not covered by the project.

Mitomap GenBank AF: 0.0 AC: 0

Gnomad homoplasmic AF: 0.000071 AC: 4 AN: 56429

Gnomad heteroplasmic AF: 0.000018 AC: 1 AN: 56429

Alfa AF: 0.000223 Hom.: 1

Mitomap

EXIT+more-/-bilateral-optic-neuropathy

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Mitochondrial disease Pathogenic:1

Pathogenic, no assertion criteria provided

in vitro

Service de Génétique Médicale, Centre Hospitalier Universitaire de Nice-Université Côte d'Azur

Oct 01, 2019

Our patient had the variant m.9166T>C, p.Phe214Leu withProximal muscle weakness, exercise intolerance, myalgia, episodic rhabdomyolysis, and hyperlactatemia -

Optic neuropathy Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Center for Neuroscience and Cell Biology, University of Coimbra, Portugal

Nov 21, 2016

- -

Leigh syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine

Oct 17, 2019

The NC_012920.1:m.9166T>C (YP_003024031.1:p.Phe214Leu) variant in MTATP6 gene is interpretated to be a Uncertain Significance variant based on the modified ACMG guidelines (unpublished). This variant meets the following evidence codes: PP3, PP7 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Apogee2	Uncertain	0.42
Hmtvar	Pathogenic	0.85
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Uncertain	0.10	D
DEOGEN2	Benign	0.38	T
LIST_S2	Uncertain	0.88	D
MutationAssessor	Pathogenic	4.6	H
PROVEAN	Pathogenic	-5.2	D
Sift4G	Uncertain	0.0080	D
GERP RS		5.0
Varity_R		0.88

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1057516063; hg19: chrM-9167;