chrM-8527-A-G

Variant names:

• chrM-8527-A-G
• rs878853003
• ENST00000361899.2:c.1A>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 10P and 12B. PVS1 PS1_Moderate BP6_Very_Strong BS2

The ENST00000361899.2(MT-ATP6):​c.1A>G​(p.Met1?) variant causes a initiator codon change. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency: Mitomap GenBank: 𝑓 0.0040 (AC: 245)
• Consequence: MT-ATP6 ENST00000361899.2 initiator_codon
• Scores: Apogee2 Benign 0.23
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2 Neuromuscular-disorder+-possible-helper-mutation
• Conservation: PhyloP100: 5.91
• Publications: 4 publications found

Genes affected

MT-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]

MT-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]

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

TRNK Gene-Disease associations (from GenCC):

• Leigh syndrome

  Inheritance: Mitochondrial Classification: DEFINITIVE Submitted by: ClinGen
• mitochondrial disease

  Inheritance: Mitochondrial Classification: DEFINITIVE Submitted by: ClinGen
• maternally-inherited cardiomyopathy and hearing loss

  Inheritance: Mitochondrial Classification: SUPPORTIVE Submitted by: Orphanet
• MERRF syndrome

  Inheritance: Mitochondrial Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PS1: Another start lost variant in ENST00000361899.2 (MT-ATP6) was described as [Likely_pathogenic] in ClinVar
• BP6: Variant M-8527-A-G is Benign according to our data. Variant chrM-8527-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 235294.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomadMitoHomoplasmic at 736

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000361899.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MT-ATP6	ENST00000361899.2	TSL:6	c.1A>G	p.Met1?	initiator_codon	Exon 1 of 1	ENSP00000354632.2
	MT-ATP8	ENST00000361851.1	TSL:6	c.162A>G	p.Lys54Lys	synonymous	Exon 1 of 1	ENSP00000355265.1
	MT-TK	ENST00000387421.1	TSL:6	n.*163A>G		downstream_gene	N/A

Frequencies

Mitomap GenBank AF: 0.0040 AC: 245

Gnomad homoplasmic AF: 0.013 AC: 736 AN: 56430

Gnomad heteroplasmic AF: 0.000018 AC: 1 AN: 56430

Alfa AF: 0.00156 Hom.: 7

Mitomap

Disease(s): Neuromuscular-disorder+-possible-helper-mutation

Status: Reported

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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.8527A>G (YP_003024031.1:p.Met1Val) 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, BS2

not provided Benign:1

Mar 18, 2016

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
Apogee2	Benign	0.23
Hmtvar	Pathogenic	0.53
BayesDel_addAF	Benign	-0.27	T
DEOGEN2	Benign	0.22	T
LIST_S2	Uncertain	0.90	D
PhyloP100		5.9
PROVEAN	Uncertain	-3.3	D
Sift4G	Pathogenic	0.0010	D
GERP RS		3.7
Varity_R		0.72
Mutation Taster		=55/145	disease causing

Other links and lift over

dbSNP: rs878853003; hg19: chrM-8528;