M-8519-G-A

Variant names:

• chrM-8519-G-A
• rs878853091
• ENST00000361851.1:c.154G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4 BP6_Very_Strong BS2

The ENST00000361851.1(MT-ATP8):​c.154G>A​(p.Glu52Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E52G) has been classified as Likely benign.

• Frequency: Mitomap GenBank: 𝑓 0.0026 (AC: 159)
• Consequence: MT-ATP8 ENST00000361851.1 missense
• Scores: Apogee2 Benign 0.16
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3 Possible-susceptibility-to-bullous-pemphigoid
• Conservation: PhyloP100: -0.0270
• Publications: 10 publications found

Genes affected

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]

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-CO2 (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)

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: Benign. The variant received -13 ACMG points.

• BP4: Apogee2 supports a benign effect, 0.15815336 < 0.5 .
• BP6: Variant M-8519-G-A is Benign according to our data. Variant chrM-8519-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 235671.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomadMitoHomoplasmic at 144

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP8	unassigned_transcript_4804	c.154G>A	p.Glu52Lys	missense_variant	Exon 1 of 1
ATP6	unassigned_transcript_4805	c.-8G>A		upstream_gene_variant
COX2	unassigned_transcript_4802	c.*250G>A		downstream_gene_variant
TRNK	unassigned_transcript_4803	c.*155G>A		downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MT-ATP8	ENST00000361851.1	c.154G>A	p.Glu52Lys	missense_variant	Exon 1 of 1	6		ENSP00000355265.1
MT-ATP6	ENST00000361899.2	c.-8G>A		upstream_gene_variant		6		ENSP00000354632.2
MT-CO2	ENST00000361739.1	c.*250G>A		downstream_gene_variant		6		ENSP00000354876.1
MT-TK	ENST00000387421.1	n.*155G>A		downstream_gene_variant		6

Frequencies

Mitomap GenBank AF: 0.0026 AC: 159

Gnomad homoplasmic AF: 0.0026 AC: 144 AN: 56419

Gnomad heteroplasmic AF: 0.00012 AC: 7 AN: 56419

Alfa AF: 0.00378 Hom.: 17

Mitomap

Disease(s): Possible-susceptibility-to-bullous-pemphigoid

Status: Reported

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Oct 08, 2015

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 27, 2022

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Likely benign

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.8519G>A (YP_003024030.1:p.Glu52Lys) variant in MTATP8 gene is interpretated to be a Benign variant based on the modified ACMG guidelines (unpublished). This variant meets the following evidence codes: BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Apogee2	Benign	0.16
Hmtvar	Pathogenic	0.80
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.36	T
DEOGEN2	Benign	0.12	T
LIST_S2	Benign	0.79	T
PhyloP100		-0.027
PROVEAN	Uncertain	-3.1	D
Sift	Uncertain	0.028	D
Sift4G	Benign	0.068	T
GERP RS		1.8
Varity_R		0.29

Other links and lift over

dbSNP: rs878853091; hg19: chrM-8520;