chrM-8803-A-T

Variant names:

• chrM-8803-A-T
• rs878853020
• unassigned_transcript_4805:c.277A>T

Variant summary

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

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

• Frequency: Mitomap GenBank: 𝑓 0.00010 (AC: 8)
• Consequence: ATP6 missense
• Scores: Apogee2 Benign 0.14
• Clinical Significance: Uncertain significance reviewed by expert panel U:2 B:1 No linked disesase in Mitomap
• Conservation: PhyloP100: 7.09

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 Benign. Variant got -8 ACMG points.

• BP6: Variant M-8803-A-T is Benign according to our data. Variant chrM-8803-A-T is described in ClinVar as [Uncertain_significance]. Clinvar id is 235370.Status of the report is reviewed_by_expert_panel, 3 stars. We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=2}.
• BS2: High AC in GnomadMitoHomoplasmic at 22

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP6	unassigned_transcript_4805	c.277A>T	p.Thr93Ser	missense_variant	Exon 1 of 1
ATP8	unassigned_transcript_4804	c.*231A>T		downstream_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: 0.00010 AC: 8

Gnomad homoplasmic AF: 0.00039 AC: 22 AN: 56434

Gnomad heteroplasmic AF: 0.0 AC: 0 AN: 56434

Alfa AF: 0.000224 Hom.: 1

Mitomap

No disease associated.

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2 Benign:1

Revision: reviewed by expert panel

Submissions by phenotype

Mitochondrial disease Uncertain:1

Jul 10, 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.8803A>T variant in MT-ATP6 was reviewed by the Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel on July 10, 2023. This variant has been reported twice in the medical literature in affected individuals but there was no attribution of pathogenic involvement in either case (one case had Leber Hereditary Optic Neuropathy, PMID 15465027; one case had Alzheimer disease, PMID 20700462). There are no other individuals or families with primary mitochondrial disease with this variant reported in the medical literature to our knowledge. This variant is present at low frequency in population databases. The frequency in gnomAD v3.1.2 was 22/56,434 (0.039%) with all 22 being homoplasmic and in top level haplogroup H. The frequency in the MITOMAP GenBank sequences was 8/59,389 (0.013%); all eight of these individuals (100%) are in H5a haplogroup, with one of them being the individual with Alzheimer disease discussed above. The frequency of homoplasmic occurrences in the Helix dataset was 159/195,983 (0.081%); 152 of these Helix variants were in haplogroup H; seven were in haplogroup U. An additional five variants were reported as heteroplasmic; these were all in haplogroup H. Of note, the individual with Leber Hereditary Optic Neuropathy discussed above types to haplogroup U1a. Therefore, the frequency of this variant meets neither criteria for pathogenicity (<0.002%) nor benign (>0.5%). The computational predictor APOGEE gives a consensus rating of benign with scores of 0.37 (“neutral”) in APOGEE1 and 0.101 (“likely benign” in APOGEE2; Min=0, Max=1), predicting no impact on gene function (BP4). There are no cybrids, single fiber studies, or other functional assays found in the literature for this variant to date. 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 July 10, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied: BP4. -

not provided Uncertain:1

May 26, 2015

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: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The NC_012920.1:m.8803A>T (YP_003024031.1:p.Thr93Ser) variant in MTATP6 gene is interpretated to be a Benign variant based on the modified ACMG guidelines (unpublished). This variant meets the following evidence codes: BS1, BS4 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Apogee2	Benign	0.14
Hmtvar	Pathogenic	0.71
AlphaMissense	Uncertain	0.34
BayesDel_addAF	Benign	-0.10	T
DEOGEN2	Benign	0.11	T
LIST_S2	Benign	0.62	T
MutationAssessor	Pathogenic	3.3	M
PROVEAN	Uncertain	-3.5	D
Sift4G	Pathogenic	0.0010	D
GERP RS		3.5
Varity_R		0.77

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs878853020; hg19: chrM-8804;