chrM-8540-T-C

Variant names:

• chrM-8540-T-C
• rs878852987
• ENST00000361899.2:c.14T>C

Variant summary

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

The ENST00000361899.2(MT-ATP6):​c.14T>C​(p.Leu5Pro) variant causes a missense change involving the alteration of a conserved nucleotide. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. L5L) has been classified as Benign.

• Frequency: Mitomap GenBank: 𝑓 0.00010 (AC: 7)
• Consequence: MT-ATP6 ENST00000361899.2 missense
• Scores: Apogee2 Uncertain 0.42
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2 No linked disesase in Mitomap
• Conservation: PhyloP100: 7.70
• Publications: 6 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-ATP8 (HGNC:7415): (mitochondrially encoded ATP synthase 8) 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 multiple sclerosis and urinary bladder cancer. [provided by Alliance of Genome Resources, Apr 2022]

TRNK (HGNC:7489): (mitochondrially encoded tRNA lysine)

TRNK Gene-Disease associations (from GenCC):

• Leigh syndrome

  Inheritance: Mitochondrial Classification: DEFINITIVE Submitted by: ClinGen
• mitochondrial disease

  Inheritance: Mitochondrial Classification: DEFINITIVE Submitted by: ClinGen
• maternally-inherited cardiomyopathy and hearing loss

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

  Inheritance: Mitochondrial Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Apogee2 supports a benign effect, 0.4194986 < 0.5 .
• BS2: High AC in GnomadMitoHomoplasmic at 7

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.14T>C	p.Leu5Pro	missense	Exon 1 of 1	ENSP00000354632.2	P00846
	MT-ATP8	ENST00000361851.1	TSL:6	c.175T>C	p.Cys59Arg	missense	Exon 1 of 1	ENSP00000355265.1	P03928
	MT-TK	ENST00000387421.1	TSL:6	n.*176T>C		downstream_gene	N/A

Frequencies

Mitomap GenBank AF: 0.00010 AC: 7

Gnomad homoplasmic AF: 0.00012 AC: 7 AN: 56430

Gnomad heteroplasmic AF: 0.0 AC: 0 AN: 56430

Mitomap

No disease associated.

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Leigh syndrome (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
Apogee2	Uncertain	0.42
Hmtvar	Benign	0.26
AlphaMissense	Uncertain	0.48
BayesDel_addAF	Benign	-0.22	T
DEOGEN2	Benign	0.082	T
LIST_S2	Benign	0.47	T
PhyloP100		7.7
PROVEAN	Benign	-1.6	N
Sift	Benign	0.16	T
Sift4G	Pathogenic	0.0	D
GERP RS		5.1
Varity_R		0.75
Mutation Taster		=85/15	polymorphism

Other links and lift over

dbSNP: rs878852987; hg19: chrM-8541;