rs1057516063

Variant names:

• chrM-9166-T-C
• rs1057516063
• ENST00000361899.2:c.640T>C

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 4P and 5B. PM1 PM2 BP4 BS2

The ENST00000361899.2(MT-ATP6):​c.640T>C​(p.Phe214Leu) 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. F214S) has been classified as Uncertain significance.

• Frequency: Mitomap GenBank: 𝑓 0.0 (AC: 0)
• Consequence: MT-ATP6 ENST00000361899.2 missense
• Scores: Apogee2 Uncertain 0.42
• Clinical Significance: Uncertain significance criteria provided, single submitter P:2 U:1 EXIT+more-/-bilateral-optic-neuropathy
• Conservation: PhyloP100: 5.95
• Publications: 1 publications found

Genes affected

MT-ATP6 (HGNC:7414): (mitochondrially encoded ATP synthase 6) Contributes to proton-transporting ATP synthase activity, rotational mechanism. Involved in mitochondrial ATP synthesis coupled proton transport. Part of mitochondrial proton-transporting ATP synthase complex. Implicated in Leber hereditary optic neuropathy; NARP syndrome; Parkinson's disease; multiple sclerosis; and systemic lupus erythematosus. [provided by Alliance of Genome Resources, Apr 2022]

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 -1 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 7 benign, 7 uncertain in ENST00000361899.2
• PM2: Very low frequency in mitomap database: 0.0
• BP4: Apogee2 supports a benign effect, 0.42470115 < 0.5 .
• BS2: High AC in GnomadMitoHomoplasmic at 4

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000361899.2. 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-ATP6	ENST00000361899.2	TSL:6	c.640T>C	p.Phe214Leu	missense	Exon 1 of 1	ENSP00000354632.2
	MT-CO3	ENST00000362079.2	TSL:6	c.-41T>C		upstream_gene	N/A	ENSP00000354982.2

Frequencies

Mitomap GenBank AF: 0.0 AC: 0

Gnomad homoplasmic AF: 0.000071 AC: 4 AN: 56429

Gnomad heteroplasmic AF: 0.000018 AC: 1 AN: 56429

Alfa AF: 0.000223 Hom.: 1

Mitomap

Disease(s): EXIT+more-/-bilateral-optic-neuropathy

Status: Reported

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Leigh syndrome (1)
1	-	-	Mitochondrial disease (1)
1	-	-	Optic neuropathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
Apogee2	Uncertain	0.42
Hmtvar	Pathogenic	0.85
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Uncertain	0.10	D
DEOGEN2	Benign	0.38	T
LIST_S2	Uncertain	0.88	D
MutationAssessor	Pathogenic	4.6	H
PhyloP100		5.9
PROVEAN	Pathogenic	-5.2	D
Sift4G	Uncertain	0.0080	D
GERP RS		5.0
Varity_R		0.88
Mutation Taster		=34/66	disease causing

Other links and lift over

dbSNP: rs1057516063; hg19: chrM-9167;