chrM-14279-G-A

Variant names:

• chrM-14279-G-A
• rs869025187
• ENST00000361681.2:c.395C>T
• MT-ND6 p.Ser132Leu

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The ENST00000361681.2(MT-ND6):​c.395C>T​(p.Ser132Leu) 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S132A) has been classified as Likely benign.

• Frequency: Mitomap GenBank: 𝑓 0.00010 (AC: 7)
• Consequence: MT-ND6 ENST00000361681.2 missense
• Scores: Apogee2 Benign 0.060
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1 O:1 LHON
• Conservation: PhyloP100: 0.385
• Publications: 15 publications found

Genes affected

MT-ND6 (HGNC:7462): (mitochondrially encoded NADH dehydrogenase 6) Enables NADH dehydrogenase (ubiquinone) activity. Involved in mitochondrial electron transport, NADH to ubiquinone and mitochondrial respiratory chain complex I assembly. Predicted to be located in mitochondrial inner membrane. Implicated in Leber hereditary optic neuropathy; Leigh disease; and spinal muscular atrophy with lower extremity predominante 2B. [provided by Alliance of Genome Resources, Apr 2022]

MT-ND5 (HGNC:7461): (mitochondrially encoded NADH dehydrogenase 5) Enables NADH dehydrogenase (ubiquinone) activity. Involved in mitochondrial electron transport, NADH to ubiquinone and mitochondrial respiratory chain complex I assembly. Part of mitochondrial respiratory chain complex I. Implicated in Leber hereditary optic neuropathy; Leigh disease; and MELAS syndrome. [provided by Alliance of Genome Resources, Apr 2022]

MT-ND5 Gene-Disease associations (from GenCC):

• Leigh syndrome

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

  Inheritance: Mitochondrial Classification: DEFINITIVE Submitted by: ClinGen
• Leber hereditary optic neuropathy

  Inheritance: Mitochondrial Classification: STRONG, SUPPORTIVE Submitted by: G2P, Orphanet
• maternally-inherited Leigh syndrome

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

  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 -1 ACMG points.

• BP4: Apogee2 supports a benign effect, 0.060099654 < 0.5 .

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000361681.2. 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-ND6	ENST00000361681.2	TSL:6	c.395C>T	p.Ser132Leu	missense	Exon 1 of 1	ENSP00000354665.2	P03923
	MT-ND5	ENST00000361567.2	TSL:6	c.*131G>A		downstream_gene	N/A	ENSP00000354813.2	P03915

Frequencies

Mitomap GenBank AF: 0.00010 AC: 7

Gnomad homoplasmic AF: 0.000053 AC: 3 AN: 56417

Gnomad heteroplasmic AF: 0.000071 AC: 4 AN: 56417

Mitomap

Disease(s): LHON

Status: Reported

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Leigh syndrome (1)
-	-	-	Leber optic atrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
Apogee2	Benign	0.060
Hmtvar	Benign	0.16
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.53	T
DEOGEN2	Benign	0.18	T
LIST_S2	Benign	0.57	T
MutationAssessor	Benign	0.26	N
PhyloP100		0.39
PROVEAN	Benign	-0.21	N
Sift	Benign	0.030	D
Sift4G	Benign	0.65	T
Varity_R		0.073
Mutation Taster		=100/0	polymorphism

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs869025187;

hg19: chrM-14280;

COSMIC: COSV62377821;

COSMIC: COSV62377821;