M-8969-G-C

Variant names:

• chrM-8969-G-C
• rs794726857
• ENST00000361899.2:c.443G>C

Variant summary

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

The ENST00000361899.2(MT-ATP6):​c.443G>C​(p.Ser148Thr) 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. S148G) has been classified as Uncertain significance.

• Frequency: Mitomap GenBank: 𝑓 0.0 (AC: 0)
• Consequence: MT-ATP6 ENST00000361899.2 missense
• Scores: Apogee2 Pathogenic 0.67
• Clinical Significance: Not reported in ClinVar Mitochondrial-myopathy+-lactic-acidosis-and-sideroblastic-anemia-(MLASA)-/-IgG-nephropathy,Suspected-mito-disease
• Conservation: PhyloP100: 9.61
• Publications: 10 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 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-8969-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 191364.Status of the report is reviewed_by_expert_panel, 3 stars.
• PP3: Apogee2 supports a deletorius effect, 0.674522 >= 0.5 .

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
There are no transcript annotations for this variant.

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MT-ATP6	ENST00000361899.2	TSL:6	c.443G>C	p.Ser148Thr	missense	Exon 1 of 1	ENSP00000354632.2
	MT-CO3	ENST00000362079.2	TSL:6	c.-238G>C		upstream_gene	N/A	ENSP00000354982.2

Frequencies

Mitomap GenBank AF: 0.0 AC: 0

Gnomad homoplasmic AF: 0.000053 AC: 3 AN: 56433

Gnomad heteroplasmic AF: 0.000018 AC: 1 AN: 56433

Mitomap

Disease(s): Mitochondrial-myopathy+-lactic-acidosis-and-sideroblastic-anemia-(MLASA)-/-IgG-nephropathy,Suspected-mito-disease

Status: Cfrm-[LP],Reported

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
Apogee2	Pathogenic	0.67
Hmtvar	Pathogenic	0.82
AlphaMissense	Pathogenic	0.73
BayesDel_addAF	Benign	-0.037	T
DEOGEN2	Benign	0.22	T
LIST_S2	Benign	0.72	T
MutationAssessor	Pathogenic	5.3	H
PhyloP100		9.6
PROVEAN	Uncertain	-2.7	D
Sift4G	Pathogenic	0.0	D
GERP RS		4.9
Varity_R		0.92

Other links and lift over

dbSNP: rs794726857; hg19: chrM-8970;