rs878853096

Variant names:

• chrM-9152-T-C
• rs878853096
• unassigned_transcript_4805:c.626T>C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP6_Strong BS2

In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★★).

• Frequency: Mitomap GenBank: 𝑓 0.00030 (AC: 17)
• Consequence: ATP6 missense
• Scores: Apogee2 Pathogenic 0.57
• Clinical Significance: Uncertain significance reviewed by expert panel U:2 B:1 O:1 Patient-with-suspected-mitochondrial-disease
• Conservation: PhyloP100: 7.67

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]

COX3 (HGNC:7422): (mitochondrially encoded cytochrome c oxidase III) Predicted to enable electron transfer activity and oxidoreduction-driven active transmembrane transporter activity. Involved in respiratory chain complex IV assembly. Part of respiratory chain complex IV. Implicated in MELAS syndrome. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP6: Variant M-9152-T-C is Benign according to our data. Variant chrM-9152-T-C is described in ClinVar as [Uncertain_significance]. Clinvar id is 235698.Status of the report is reviewed_by_expert_panel, 3 stars. We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2, not_provided=1}.
• BS2: High AC in GnomadMitoHomoplasmic at 7

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP6	unassigned_transcript_4805	c.626T>C	p.Ile209Thr	missense_variant	Exon 1 of 1
COX3	unassigned_transcript_4806	c.-55T>C		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	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: 0.00030 AC: 17

Gnomad homoplasmic AF: 0.00012 AC: 7 AN: 56430

Gnomad heteroplasmic AF: 0.000089 AC: 5 AN: 56430

Alfa AF: 0.000223 Hom.: 1

Mitomap

Patient-with-suspected-mitochondrial-disease

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2 Benign:1 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Mitochondrial disease Uncertain:1

Jun 26, 2023

ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen

Significance: Uncertain significance

Review Status: reviewed by expert panel

Collection Method: curation

The m.9152T>C (p.I209T) variant in MT-ATP6 has been reported in one case to date, in an individual with autism, fatigue, reflux, and constipation (PMID: 30763462) who had the variant present at 23% in blood. The proband's healthy mother had the variant present at 10% in blood. There are no reported de novo occurrences to our knowledge. The computational predictor APOGEE gives a consensus rating of neutral with a score of 0.47 (Min=0, Max=1), which predicts no damaging effect on gene function (BP4). There are no cybrids, single fiber studies, or other functional assays reported on this variant. In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on June 26, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): BP4. -

not provided Uncertain:1

Oct 13, 2014

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Leigh syndrome Benign:1

Oct 17, 2019

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The NC_012920.1:m.9152T>C (YP_003024031.1:p.Ile209Thr) variant in MTATP6 gene is interpretated to be a Likely Benign variant based on the modified ACMG guidelines (unpublished). This variant meets the following evidence codes: BS1, BP6 -

Mitochondrial-DNA disorder Other:1

-

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Apogee2	Pathogenic	0.57
Hmtvar	Pathogenic	0.87
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Benign	-0.0048	T
DEOGEN2	Benign	0.40	T
LIST_S2	Benign	0.77	T
MutationAssessor	Pathogenic	5.0	H
PROVEAN	Pathogenic	-4.4	D
Sift4G	Pathogenic	0.0	D
GERP RS		5.0
Varity_R		0.94

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs878853096; hg19: chrM-9153;