chrM-9478-T-C

Variant names:

• chrM-9478-T-C
• rs587776437
• ENST00000362079.2:c.272T>C

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4 BS2

The ENST00000362079.2(MT-CO3):​c.272T>C​(p.Val91Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 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. V91I) has been classified as Likely benign.

• Frequency: Mitomap GenBank: 𝑓 0.00040 (AC: 22)
• Consequence: MT-CO3 ENST00000362079.2 missense
• Scores: Apogee2 Benign 0.15
• Clinical Significance: Uncertain significance reviewed by expert panel P:1 U:3 O:1 Leigh-Disease
• Conservation: PhyloP100: 2.15
• Publications: 3 publications found

Genes affected

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-CO3 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
• Leber hereditary optic neuropathy

  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 -5 ACMG points.

• BP4: Apogee2 supports a benign effect, 0.14866045 < 0.5 .
• BS2: High AC in GnomadMitoHomoplasmic at 127

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000362079.2. 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-CO3	ENST00000362079.2	TSL:6	c.272T>C	p.Val91Ala	missense	Exon 1 of 1	ENSP00000354982.2	P00414

Frequencies

Mitomap GenBank AF: 0.00040 AC: 22

Gnomad homoplasmic AF: 0.0023 AC: 127 AN: 56427

Gnomad heteroplasmic AF: 0.000035 AC: 2 AN: 56427

Mitomap

Disease(s): Leigh-Disease

Status: Reported-[VUS]

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
1	-	-	Autosomal dominant spastic ataxia (1)
-	1	-	Mitochondrial disease (1)
-	1	-	not provided (1)
-	1	-	not specified (1)
-	-	-	Leigh syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
Apogee2	Benign	0.15
Hmtvar	Benign	0.14
AlphaMissense	Uncertain	0.55
BayesDel_addAF	Benign	-0.31	T
DEOGEN2	Benign	0.11	T
LIST_S2	Benign	0.45	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		2.2
PROVEAN	Uncertain	-3.4	D
Sift	Benign	0.047	D
Sift4G	Uncertain	0.026	D
GERP RS		5.1
Varity_R		0.23
Mutation Taster		=83/17	polymorphism

Other links and lift over

dbSNP: rs587776437; hg19: chrM-9479;