rs1057516062

Variant names:

• chrM-8418-T-C
• rs1057516062
• unassigned_transcript_4804:c.53T>C

Variant summary

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

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

• Frequency: Mitomap GenBank: 𝑓 0.0 (AC: 1)
• Consequence: ATP8 missense
• Scores: Apogee2 Benign 0.17
• Clinical Significance: Uncertain significance reviewed by expert panel P:1 U:2 Mitochondrial-Respiratory-Chain-Disorder
• Conservation: PhyloP100: 1.65

Genes affected

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]

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]

COX2 (HGNC:7421): (mitochondrially encoded cytochrome c oxidase II) Contributes to cytochrome-c oxidase activity. Predicted to be involved in mitochondrial electron transport, cytochrome c to oxygen and positive regulation of vasoconstriction. Located in mitochondrial inner membrane. Part of respiratory chain complex IV. Biomarker of Huntington's disease and stomach cancer. [provided by Alliance of Genome Resources, Apr 2022]

TRNK (HGNC:7489): (mitochondrially encoded tRNA lysine)

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 rank	MANE	Protein	UniProt
ATP8	unassigned_transcript_4804	c.53T>C	p.Leu18Pro	missense_variant	Exon 1 of 1
ATP6	unassigned_transcript_4805	c.-109T>C		upstream_gene_variant
COX2	unassigned_transcript_4802	c.*149T>C		downstream_gene_variant
TRNK	unassigned_transcript_4803	c.*54T>C		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: 0.0 AC: 1

Gnomad homoplasmic AF: 0.000071 AC: 4 AN: 56432

Gnomad heteroplasmic AF: 0.000053 AC: 3 AN: 56432

Mitomap

Mitochondrial-Respiratory-Chain-Disorder

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:2

Revision: reviewed by expert panel

Submissions by phenotype

Optic neuropathy Pathogenic:1

Nov 21, 2016

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

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified Uncertain:1

May 04, 2022

Mendelics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mitochondrial disease Uncertain:1

Nov 11, 2024

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.8418T>C (p.L18P) variant in MT-ATP8 has been reported in one individual with primary mitochondrial disease to date (PMID: 28027978), in a man with severe bilateral optic atrophy onset at age 44 years. The variant was present at homoplasmy in lymphocytes and fibroblasts. Family history information was not provided. There are no additional individuals reported with this variant to our knowledge. This variant is rare but present in population databases (Mitomap: 1/61,134; gnomAD v3.1.2: 5/46,432; Helix: 3/195,983) with a combined frequency of 0.00255%, which is slightly higher than the supporting pathogenic cutoff of 0.002% but lower than the frequency of 0.5-0.99% required for evidence of benign status. The computational predictor APOGEE gives a consensus rating of likely benign with a score of 0.175 (Min=0, Max=1), which predicts a neutral effect on gene function (BP4). There are no cybrids or single fiber studies reported on this variant although in-silico yeast modeling predicted this variant to destabilize the F0 domain of ATP8 (PMID: 37340059). 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 November 11, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): BP4. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Apogee2	Benign	0.17
Hmtvar	Pathogenic	0.77
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.35	T
DEOGEN2	Benign	0.098	T
LIST_S2	Benign	0.58	T
PROVEAN	Uncertain	-3.8	D
Sift	Benign	0.14	T
Sift4G	Benign	0.19	T
GERP RS		2.7
Varity_R		0.68

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1057516062; hg19: chrM-8419;