rs267606611

Positions:

• chrM-9438-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 2P and 11B. PS1_Moderate 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 nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt.

• 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

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]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• PS1: Transcript ENST00000362079.2 (MT-CO3) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
• 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 id 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/exons	MANE	UniProt
COX3	COX3.1	c.232G>A	p.Gly78Ser	missense_variant	1/1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MT-CO3	ENST00000362079.2	c.232G>A	p.Gly78Ser	missense_variant	1/1			P1

Frequencies

GnomAD4 exome Cov.: 0

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

Mitomap GenBank AF: 0.012 AC: 761

Gnomad homoplasmic AF: 0.0034 AC: 192 AN: 56418

Gnomad heteroplasmic AF: 0.00011 AC: 6 AN: 56418

Alfa AF: 0.00233 Hom.: 11

Mitomap

LHON-/-gout

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1 Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Leber optic atrophy Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 01, 1995

- -

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.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
MutationTaster	Benign	7.8e-8	A
PROVEAN	Uncertain	-4.3	D
Sift	Benign	0.038	D
Sift4G	Uncertain	0.033	D
GERP RS		3.5
Varity_R		0.31

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs267606611; hg19: chrM-9439;