rs200809063

Positions:

• chrM-9966-G-A
• chrM-9966-G-C

Variant summary

Our verdict is Benign. Variant got -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 nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• 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

Genes affected

COX3 (HGNC:):

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-TG (HGNC:7486): (mitochondrially encoded tRNA glycine)

ACMG classification

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id 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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COX3	COX3.1	c.760G>A	p.Val254Ile	missense_variant	1/1
TRNG	TRNG.1			upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MT-CO3	ENST00000362079.2	c.760G>A	p.Val254Ile	missense_variant	1/1			P1
MT-TG	ENST00000387429.1			upstream_gene_variant

Frequencies

GnomAD4 exome Cov.: 0

We have no GnomAD4 genomes data on this position. Probably position not covered by the project.

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: 0.00589 Hom.: 230

Mitomap

LHON-possible-helper-variant

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Leigh syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine

Oct 17, 2019

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

Likely benign, criteria provided, single submitter

clinical testing

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

Dec 01, 2016

- -

Computational scores

Source: dbNSFP v4.3

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
MutationTaster	Benign	1.0	N
PROVEAN	Benign	0.19	N
Sift	Benign	0.11	T
Sift4G	Benign	1.0	T
GERP RS		1.7
Varity_R		0.11

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

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