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: Orphanet, G2P
• 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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COX3	unassigned_transcript_4806	c.232G>A	p.Gly78Ser	missense_variant	Exon 1 of 1
ATP6	unassigned_transcript_4805	c.*231G>A		downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MT-CO3	ENST00000362079.2	c.232G>A	p.Gly78Ser	missense_variant	Exon 1 of 1	6		ENSP00000354982.2
MT-ATP6	ENST00000361899.2	c.*231G>A		downstream_gene_variant		6		ENSP00000354632.2

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

Significance: Benign

Submissions summary: Pathogenic:1 Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Leber optic atrophy Pathogenic:1

Oct 01, 1995

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

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.9438G>A (YP_003024032.1:p.Gly78Ser) variant in MTCO3 gene is interpretated to be a Benign variant based on the modified ACMG guidelines (unpublished). This variant meets the following evidence codes: BA1 -

Computational scores

Source: dbNSFP v4.3

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;