M-14484-T-G

Variant names:

• chrM-14484-T-G
• rs199476104
• ENST00000361681.2:c.190A>C

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 6P and 1B. PM1 PM2 PM5 BP4

The ENST00000361681.2(MT-ND6):​c.190A>C​(p.Met64Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 7/11 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. M64I) has been classified as Likely pathogenic.

• Frequency: Mitomap GenBank: 𝑓 0.0 (AC: 0)
• Consequence: MT-ND6 ENST00000361681.2 missense
• Scores: Apogee2 Benign 0.081
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1 No linked disesase in Mitomap
• Conservation: PhyloP100: -1.48
• Publications: 56 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]

TRNE (HGNC:7479): (mitochondrially encoded tRNA glutamic acid)

TRNE Gene-Disease associations (from GenCC):

• mitochondrial disease

  Inheritance: Mitochondrial Classification: DEFINITIVE Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 5 uncertain in ENST00000361681.2
• PM2: Very low frequency in mitomap database: 0.0
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrM-14482-C-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 65513.Status of the report is reviewed_by_expert_panel, 3 stars.
• BP4: Apogee2 supports a benign effect, 0.08082871 < 0.5 .

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ND6	unassigned_transcript_4816	c.190A>C	p.Met64Leu	missense_variant	Exon 1 of 1
TRNE	unassigned_transcript_4817	c.*190A>C		downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MT-ND6	ENST00000361681.2	c.190A>C	p.Met64Leu	missense_variant	Exon 1 of 1	6		ENSP00000354665.2
MT-TE	ENST00000387459.1	n.*190A>C		downstream_gene_variant		6

Frequencies

Mitomap GenBank AF: 0.0 AC: 0

Mitomap

No disease associated.

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Leigh syndrome Uncertain:1

Oct 17, 2019

Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The NC_012920.1:m.14484T>G (YP_003024037.1:p.Met64Leu) variant in MTND6 gene is interpretated to be a Uncertain Significance variant based on the modified ACMG guidelines (unpublished). This variant meets the following evidence codes: PP7, BS4 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Apogee2	Benign	0.081
Hmtvar	Pathogenic	0.66
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.61	T
DEOGEN2	Benign	0.20	T
LIST_S2	Benign	0.82	T
MutationAssessor	Benign	-0.23	N
PhyloP100		-1.5
PROVEAN	Benign	0.36	N
Sift	Benign	0.28	T
Sift4G	Benign	1.0	T
GERP RS		-8.1
Varity_R		0.25
Mutation Taster		=90/10	polymorphism

Other links and lift over

dbSNP: rs199476104; hg19: chrM-14485;