chrM-8529-G-T

Variant names:

• chrM-8529-G-T
• rs267606881
• ENST00000361851.1:c.164G>T

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PM5 PP3

The ENST00000361851.1(MT-ATP8):​c.164G>T​(p.Trp55Leu) variant causes a missense change involving the alteration of a conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W55R) has been classified as Likely pathogenic.

• Frequency: Mitomap GenBank: 𝑓 0.0 (AC: 0)
• Consequence: MT-ATP8 ENST00000361851.1 missense
• Scores: Apogee2 Pathogenic 0.75
• Clinical Significance: Not reported in ClinVar No linked disesase in Mitomap
• Conservation: PhyloP100: 7.76
• Publications: 0 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]

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: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very low frequency in mitomap database: 0.0
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrM-8528-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 9640.Status of the report is reviewed_by_expert_panel, 3 stars.
• PP3: Apogee2 supports a deletorius effect, 0.74694085 >= 0.5 .

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP8	unassigned_transcript_4804	c.164G>T	p.Trp55Leu	missense_variant	Exon 1 of 1
ATP6	unassigned_transcript_4805	c.3G>T	p.Met1?	initiator_codon_variant	Exon 1 of 1
TRNK	unassigned_transcript_4803	c.*165G>T		downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MT-ATP8	ENST00000361851.1	c.164G>T	p.Trp55Leu	missense_variant	Exon 1 of 1	6		ENSP00000355265.1
MT-ATP6	ENST00000361899.2	c.3G>T	p.Met1?	initiator_codon_variant	Exon 1 of 1	6		ENSP00000354632.2
MT-TK	ENST00000387421.1	n.*165G>T		downstream_gene_variant		6

Frequencies

Mitomap GenBank AF: 0.0 AC: 0

Mitomap

No disease associated.

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Apogee2	Pathogenic	0.75
Hmtvar	Pathogenic	0.86
AlphaMissense	Uncertain	0.51
BayesDel_addAF	Uncertain	0.14	D
DEOGEN2	Benign	0.22	T
LIST_S2	Uncertain	0.90	D
PhyloP100		7.8
PROVEAN	Uncertain	-3.3	D
Sift4G	Pathogenic	0.0010	D
GERP RS		5.1
Varity_R		0.76
Mutation Taster		=12/88	disease causing

Other links and lift over

dbSNP: rs267606881; hg19: chrM-8530;