chrM-9966-G-A

Variant names:

• chrM-9966-G-A
• rs200809063
• ENST00000362079.2:c.760G>A

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4 BP6_Very_Strong BS1 BS2

The ENST00000362079.2(MT-CO3):​c.760G>A​(p.Val254Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 8/11 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V254A) has been classified as Uncertain significance.

• Frequency: Mitomap GenBank: 𝑓 0.0066 (AC: 401)
• Consequence: MT-CO3 ENST00000362079.2 missense
• Scores: Apogee2 Benign 0.039
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2 LHON-possible-helper-variant
• Conservation: PhyloP100: 0.0720
• Publications: 20 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-ND3 (HGNC:7458): (mitochondrially encoded NADH dehydrogenase 3) Enables NADH dehydrogenase (ubiquinone) activity. Involved in mitochondrial electron transport, NADH to ubiquinone. Part of mitochondrial respiratory chain complex I. Implicated in Leber hereditary optic neuropathy; Leigh disease; and Parkinson's disease. [provided by Alliance of Genome Resources, Apr 2022]

TRNG (HGNC:7486): (mitochondrially encoded tRNA glycine)

TRNG Gene-Disease associations (from GenCC):

• mitochondrial disease

  Inheritance: Mitochondrial Classification: MODERATE Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -17 ACMG points.

• BP4: Apogee2 supports a benign effect, 0.039187443 < 0.5 .
• BP6: Variant M-9966-G-A is Benign according to our data. Variant chrM-9966-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 377020.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: High frequency in mitomap database: 0.0066000004
• BS2: High AC in GnomadMitoHomoplasmic at 447

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MT-CO3	ENST00000362079.2	TSL:6	c.760G>A	p.Val254Ile	missense	Exon 1 of 1	ENSP00000354982.2
	MT-ND3	ENST00000361227.2	TSL:6	c.-93G>A		upstream_gene	N/A	ENSP00000355206.2
	MT-TG	ENST00000387429.1	TSL:6	n.-25G>A		upstream_gene	N/A

Frequencies

Mitomap GenBank AF: 0.0066 AC: 401

Gnomad homoplasmic AF: 0.0079 AC: 447 AN: 56402

Gnomad heteroplasmic AF: 0.00011 AC: 6 AN: 56402

Alfa AF: 0.00592 Hom.: 235

Mitomap

Disease(s): LHON-possible-helper-variant

Status: Reported

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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.9966G>A (YP_003024032.1:p.Val254Ile) 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

not provided Benign:1

Dec 01, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
Apogee2	Benign	0.039
Hmtvar	Benign	0.070
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.44	T
DEOGEN2	Benign	0.012	T
LIST_S2	Benign	0.48	T
MutationAssessor	Benign	-0.29	N
PhyloP100		0.072
PROVEAN	Benign	0.19	N
Sift	Benign	0.11	T
Sift4G	Benign	1.0	T
GERP RS		1.7
Varity_R		0.11
Mutation Taster		=77/23	polymorphism

Other links and lift over

dbSNP: rs200809063; hg19: chrM-9967; COSMIC: COSV100677712; COSMIC: COSV100677712;