chrM-6480-G-A

Variant names:

• chrM-6480-G-A
• rs199476128
• ENST00000361624.2:c.577G>A

Variant summary

Our verdict is Likely benign. The variant received -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
• Publications: 20 publications found

Genes affected

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]

MT-CO1 Gene-Disease associations (from GenCC):

• mitochondrial disease

  Inheritance: Mitochondrial Classification: DEFINITIVE Submitted by: ClinGen
• hereditary recurrent myoglobinuria

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• cytochrome-c oxidase deficiency disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• MELAS syndrome

  Inheritance: Mitochondrial Classification: SUPPORTIVE Submitted by: Orphanet
• mitochondrial non-syndromic sensorineural hearing loss

  Inheritance: Mitochondrial Classification: SUPPORTIVE Submitted by: Orphanet
• Leigh syndrome

  Inheritance: Mitochondrial Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -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 VariationId is 9666.
• BS2: High AC in GnomadMitoHomoplasmic at 183

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000361624.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
There are no transcript annotations for this variant.

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MT-CO1	ENST00000361624.2	TSL:6	c.577G>A	p.Val193Ile	missense	Exon 1 of 1	ENSP00000354499.2	P00395

Frequencies

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: 0.00325 Hom.: 150

Mitomap

Disease(s): Prostate-Cancer-/-enriched-in-POAG-cohort

Status: Reported

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	Leigh syndrome (1)
1	-	-	Mitochondrial complex IV deficiency, nuclear type 1 (1)
-	1	-	Mitochondrial disease (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		3.2
PROVEAN	Benign	0.35	N
Sift4G	Benign	1.0	T
GERP RS		4.5
Varity_R		0.22
Mutation Taster		=53/47	polymorphism

Other links and lift over

dbSNP: rs199476128; hg19: chrM-6481;