rs199476128

Positions:

• chrM-6480-G-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4 BP6 BS2

The ENST00000361624.2(MT-CO1):​c.577G>A​(p.Val193Ile) 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V193A) has been classified as Uncertain significance.

• Frequency: Mitomap GenBank: 𝑓 0.0026 (AC: 156)
• Consequence: MT-CO1 ENST00000361624.2 missense
• Scores: Apogee2 Benign 0.0072
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1 B:1 Prostate-Cancer-/-enriched-in-POAG-cohort
• Conservation: PhyloP100: 3.23

Genes affected

COX1 (HGNC:):

MT-CO1 (HGNC:7419): (mitochondrially encoded cytochrome c oxidase I) Contributes to cytochrome-c oxidase activity. Predicted to be involved in electron transport coupled proton transport and mitochondrial electron transport, cytochrome c to oxygen. Part of mitochondrial respiratory chain complex III and mitochondrial respiratory chain complex IV. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Apogee2 supports a benign effect, 0.0071823313 < 0.5 .
• BP6: Variant M-6480-G-A is Benign according to our data. Variant chrM-6480-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 9666.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=1}.
• BS2: High AC in GnomadMitoHomoplasmic at 183

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COX1	COX1.1	c.577G>A	p.Val193Ile	missense_variant	1/1		YP_003024028.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MT-CO1	ENST00000361624.2	c.577G>A	p.Val193Ile	missense_variant	1/1			ENSP00000354499	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: 0.0026 AC: 156

Gnomad homoplasmic AF: 0.0032 AC: 183 AN: 56425

Gnomad heteroplasmic AF: 0.00012 AC: 7 AN: 56425

Alfa AF: 0.00253 Hom.: 99

Mitomap

Prostate-Cancer-/-enriched-in-POAG-cohort

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Mitochondrial complex IV deficiency, nuclear type 1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 01, 1998

- -

Mitochondrial disease Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 18, 2019

The MT-COX1 m.6480G>A p.(Val193Ile) missense has been identified in individuals with a phenotype consistent with primary mitochondrial disease (Jaksch et al. 1998a; Jaksch et al. 1998b; Puomila et al. 2007; Cai et al. 2008). In several individuals, a second mitochondrial variant was also identified. The variant has also been reported in two of at least 851 controls, including in one individual who was homoplasmic (Jaksch et al. 1998a; Jaksch et al. 1998b; Cai et al. 2008; Dobrowolski et al. 2009; Ray et al. 2009). Based on the available evidence, the m.6480G>A variant is classified as a variant of uncertain significance for primary mitochondrial disease. -

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.6480G>A (YP_003024028.1:p.Val193Ile) variant in MTCO1 gene is interpretated to be a Benign variant based on the modified ACMG guidelines (unpublished). This variant meets the following evidence codes: BS1, BS4, BP4 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Apogee2	Benign	0.0072
Hmtvar	Benign	0.11
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.61	T
DEOGEN2	Benign	0.011	T
LIST_S2	Benign	0.67	T
MutationAssessor	Benign	-0.68	N
MutationTaster	Benign	0.00016	A
PROVEAN	Benign	0.35	N
Sift4G	Benign	1.0	T
GERP RS		4.5
Varity_R		0.22

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs199476128; hg19: chrM-6481;