chrM-8989-G-C

Variant names:

• chrM-8989-G-C
• rs587776444
• ENST00000361899.2:c.463G>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The ENST00000361899.2(MT-ATP6):​c.463G>C​(p.Ala155Pro) variant causes a missense change involving the alteration of a conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. 7/11 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A155T) has been classified as Likely benign.

• Frequency: Mitomap GenBank: Absent
• Consequence: MT-ATP6 ENST00000361899.2 missense
• Scores: Apogee2 Pathogenic 0.90
• Clinical Significance: not provided no classification provided O:1 NARP-syndrome
• Conservation: PhyloP100: 7.78
• Publications: 3 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-CO3 (HGNC:7422): (mitochondrially encoded cytochrome c oxidase III) Predicted to enable electron transfer activity and oxidoreduction-driven active transmembrane transporter activity. Involved in respiratory chain complex IV assembly. Part of respiratory chain complex IV. Implicated in MELAS syndrome. [provided by Alliance of Genome Resources, Apr 2022]

MT-CO3 Gene-Disease associations (from GenCC):

• mitochondrial disease

  Inheritance: Mitochondrial Classification: DEFINITIVE Submitted by: ClinGen
• hereditary recurrent myoglobinuria

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• cytochrome-c oxidase deficiency disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Leber hereditary optic neuropathy

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

  Inheritance: Mitochondrial Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: No frequency data in Mitomap. Probably very rare.
• PP3: Apogee2 supports a deletorius effect, 0.8954756 >= 0.5 .

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP6	unassigned_transcript_4805	c.463G>C	p.Ala155Pro	missense_variant	Exon 1 of 1
COX3	unassigned_transcript_4806	c.-218G>C		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MT-ATP6	ENST00000361899.2	c.463G>C	p.Ala155Pro	missense_variant	Exon 1 of 1	6		ENSP00000354632.2
MT-CO3	ENST00000362079.2	c.-218G>C		upstream_gene_variant		6		ENSP00000354982.2

Frequencies

Mitomap GenBank The variant is not present, suggesting it is rare .

Mitomap

Disease(s): NARP-syndrome

Status: Reported

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

Leigh syndrome Other:1

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GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Apogee2	Pathogenic	0.90
Hmtvar	Pathogenic	0.91
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Uncertain	0.055	T
DEOGEN2	Benign	0.30	T
LIST_S2	Uncertain	0.88	D
MutationAssessor	Pathogenic	4.3	H
PhyloP100		7.8
PROVEAN	Pathogenic	-4.4	D
Sift4G	Uncertain	0.015	D
GERP RS		4.1
Varity_R		0.97

Other links and lift over

dbSNP: rs587776444; hg19: chrM-8990;