M-9804-G-C

Position:

• chrM-9804-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2 PM5 BP4

The ENST00000362079.2(MT-CO3):​c.598G>C​(p.Ala200Pro) variant causes a missense change. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A200T) has been classified as Uncertain significance.

• Frequency: Mitomap GenBank: 𝑓 0.0 (AC: 2)
• Consequence: MT-CO3 ENST00000362079.2 missense
• Scores: Apogee2 Uncertain 0.46
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1 No linked disesase in Mitomap
• Conservation: PhyloP100: 4.01

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very low frequency in mitomap database: 0.0
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• BP4: Apogee2 supports a benign effect, 0.4596199 < 0.5 .

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COX3	COX3.1	c.598G>C	p.Ala200Pro	missense_variant	1/1		YP_003024032.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MT-CO3	ENST00000362079.2	c.598G>C	p.Ala200Pro	missense_variant	1/1			ENSP00000354982	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: 0.0 AC: 2

Mitomap

No disease associated.

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Leigh syndrome Uncertain:1

Uncertain significance, 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.9804G>C (YP_003024032.1:p.Ala200Pro) variant in MTCO3 gene is interpretated to be a Uncertain Significance variant based on the modified ACMG guidelines (unpublished). This variant meets the following evidence codes: PP4 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Apogee2	Uncertain	0.46
Hmtvar	Pathogenic	0.84
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Benign	-0.31	T
DEOGEN2	Benign	0.17	T
LIST_S2	Benign	0.64	T
MutationAssessor	Pathogenic	5.0	H
MutationTaster	Benign	1.0	N
PROVEAN	Pathogenic	-4.5	D
Sift	Uncertain	0.0020	D
Sift4G	Pathogenic	0.0010	D
GERP RS		4.3
Varity_R		0.85

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs200613617; hg19: chrM-9805;