rs267606611

Variant names:

• chrM-9438-G-A
• rs267606611
• ENST00000362079.2:c.232G>A

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4 BP6_Moderate BA1

The ENST00000362079.2(MT-CO3):​c.232G>A​(p.Gly78Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G78D) has been classified as Uncertain significance.

• Frequency: Mitomap GenBank: 𝑓 0.012 (AC: 761)
• Consequence: MT-CO3 ENST00000362079.2 missense
• Scores: Apogee2 Uncertain 0.44
• Clinical Significance: Benign criteria provided, single submitter P:1 B:1 LHON-/-gout
• Conservation: PhyloP100: 2.25
• Publications: 16 publications found

Genes affected

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-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-ATP6 Gene-Disease associations (from GenCC):

• Leigh syndrome

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

  Inheritance: Mitochondrial Classification: DEFINITIVE Submitted by: ClinGen
• NARP syndrome

  Inheritance: Mitochondrial Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet
• familial infantile bilateral striatal necrosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• mitochondrial proton-transporting ATP synthase complex deficiency

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

  Inheritance: Mitochondrial Classification: SUPPORTIVE Submitted by: Orphanet
• maternally-inherited Leigh syndrome

  Inheritance: Mitochondrial Classification: SUPPORTIVE Submitted by: Orphanet
• maternally-inherited spastic paraplegia

  Inheritance: Mitochondrial Classification: SUPPORTIVE Submitted by: Orphanet
• periodic paralysis with later-onset distal motor neuropathy

  Inheritance: Mitochondrial Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -11 ACMG points.

• BP4: Apogee2 supports a benign effect, 0.43836996 < 0.5 .
• BP6: Variant M-9438-G-A is Benign according to our data. Variant chrM-9438-G-A is described in ClinVar as Benign. ClinVar VariationId is 9651.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: High frequency in mitomap database: 0.0124

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000362079.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
There are no transcript annotations for this variant.

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MT-CO3	ENST00000362079.2	TSL:6	c.232G>A	p.Gly78Ser	missense	Exon 1 of 1	ENSP00000354982.2	P00414
	MT-ATP6	ENST00000361899.2	TSL:6	c.*231G>A		downstream_gene	N/A	ENSP00000354632.2	P00846

Frequencies

Mitomap GenBank AF: 0.012 AC: 761

Gnomad homoplasmic AF: 0.0034 AC: 192 AN: 56418

Gnomad heteroplasmic AF: 0.00011 AC: 6 AN: 56418

Alfa AF: 0.00295 Hom.: 48

Mitomap

Disease(s): LHON-/-gout

Status: Conflicting-reports

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Leber optic atrophy (1)
-	-	1	Leigh syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
Apogee2	Uncertain	0.44
Hmtvar	Benign	0.27
AlphaMissense	Benign	0.30
BayesDel_addAF	Benign	-0.30	T
DEOGEN2	Benign	0.11	T
LIST_S2	Benign	0.79	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		2.3
PROVEAN	Uncertain	-4.3	D
Sift	Benign	0.038	D
Sift4G	Uncertain	0.033	D
GERP RS		3.5
Varity_R		0.31
Mutation Taster		=50/50

Other links and lift over

dbSNP: rs267606611; hg19: chrM-9439;