M-8540-T-C

Position:

• chrM-8540-T-C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

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

• Frequency: Mitomap GenBank: 𝑓 0.00010 (AC: 7)
• Consequence: ATP6 missense
• Scores: Apogee2 Uncertain 0.42
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2 No linked disesase in Mitomap
• Conservation: PhyloP100: 7.70

Genes affected

ATP6 (HGNC:7414): (mitochondrially encoded ATP synthase 6) Contributes to proton-transporting ATP synthase activity, rotational mechanism. Involved in mitochondrial ATP synthesis coupled proton transport. Part of mitochondrial proton-transporting ATP synthase complex. Implicated in Leber hereditary optic neuropathy; NARP syndrome; Parkinson's disease; multiple sclerosis; and systemic lupus erythematosus. [provided by Alliance of Genome Resources, Apr 2022]

ATP8 (HGNC:7415): (mitochondrially encoded ATP synthase 8) Contributes to proton-transporting ATP synthase activity, rotational mechanism. Involved in mitochondrial ATP synthesis coupled proton transport. Part of mitochondrial proton-transporting ATP synthase complex. Implicated in multiple sclerosis and urinary bladder cancer. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• BS2: High AC in GnomadMitoHomoplasmic at 7

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATP6	unassigned_transcript_4805	c.14T>C	p.Leu5Pro	missense_variant	1/1
ATP8	unassigned_transcript_4804	c.175T>C	p.Cys59Arg	missense_variant	1/1

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: 0.00010 AC: 7

Gnomad homoplasmic AF: 0.00012 AC: 7 AN: 56430

Gnomad heteroplasmic AF: 0.0 AC: 0 AN: 56430

Mitomap

No disease associated.

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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.8540T>C (YP_003024031.1:p.Leu5Pro) variant in MTATP6 gene ( also (YP_003024030.1:p.Cys59Arg) variant in MTATP8 gene ) is interpretated to be a Uncertain Significance variant based on the modified ACMG guidelines (unpublished). This variant meets the following evidence codes: PP3 -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Jan 11, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Apogee2	Uncertain	0.42
Hmtvar	Benign	0.26
AlphaMissense	Uncertain	0.48
BayesDel_addAF	Benign	-0.22	T
DEOGEN2	Benign	0.082	T
LIST_S2	Benign	0.47	T
PROVEAN	Benign	-1.6	N
Sift	Benign	0.16	T
Sift4G	Pathogenic	0.0	D
GERP RS		5.1
Varity_R		0.34

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs878852987; hg19: chrM-8541;