rs199476121

Variant names:

• chrM-4136-A-G
• rs199476121
• ENST00000361390.2:c.830A>G

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 1P and 12B. PP3 BP6_Very_Strong BS2

The ENST00000361390.2(MT-ND1):​c.830A>G​(p.Tyr277Cys) variant causes a missense change. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y277H) has been classified as Benign.

• Frequency: Mitomap GenBank: 𝑓 0.0012 (AC: 71)
• Consequence: MT-ND1 ENST00000361390.2 missense
• Scores: Apogee2 Pathogenic 0.75
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts P:1 B:2 LHON
• Conservation: PhyloP100: 7.06
• Publications: 21 publications found

Genes affected

MT-ND1 (HGNC:7455): (mitochondrially encoded NADH dehydrogenase 1) Enables NADH dehydrogenase (ubiquinone) activity. Involved in mitochondrial electron transport, NADH to ubiquinone and mitochondrial respiratory chain complex I assembly. Located in mitochondrial membrane. Part of mitochondrial respiratory chain complex I. Implicated in several diseases, including MELAS syndrome; neurodegenerative disease (multiple); optic nerve disease (multiple); toxic shock syndrome; and type 2 diabetes mellitus. Biomarker of Alzheimer's disease; Parkinson's disease; and multiple sclerosis. [provided by Alliance of Genome Resources, Apr 2022]

TRNI (HGNC:7488): (mitochondrially encoded tRNA isoleucine)

TRNQ (HGNC:7495): (mitochondrially encoded tRNA glutamine)

TRNQ Gene-Disease associations (from GenCC):

• mitochondrial disease

  Inheritance: Mitochondrial Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -11 ACMG points.

• PP3: Apogee2 supports a deletorius effect, 0.7474082 >= 0.5 .
• BP6: Variant M-4136-A-G is Benign according to our data. Variant chrM-4136-A-G is described in ClinVar as Benign. ClinVar VariationId is 9727.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomadMitoHomoplasmic at 35

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000361390.2. 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-ND1	ENST00000361390.2	TSL:6	c.830A>G	p.Tyr277Cys	missense	Exon 1 of 1	ENSP00000354687.2	P03886
	MT-TI	ENST00000387365.1	TSL:6	n.-127A>G		upstream_gene	N/A
	MT-TQ	ENST00000387372.1	TSL:6	n.*193T>C		downstream_gene	N/A

Frequencies

Mitomap GenBank AF: 0.0012 AC: 71

Gnomad homoplasmic AF: 0.00062 AC: 35 AN: 56415

Gnomad heteroplasmic AF: 0.00011 AC: 6 AN: 56415

Alfa AF: 0.000112 Hom.: 0

Mitomap

Disease(s): LHON

Status: Reported---possibly-synergistic

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
Apogee2	Pathogenic	0.75
Hmtvar	Pathogenic	0.76
AlphaMissense	Uncertain	0.45
BayesDel_addAF	Benign	-0.0095	T
DEOGEN2	Benign	0.15	T
LIST_S2	Benign	0.81	T
MutationAssessor	Pathogenic	4.1	H
PhyloP100		7.1
PROVEAN	Pathogenic	-8.1	D
Sift4G	Uncertain	0.0040	D
GERP RS		4.5
Varity_R		0.89
Mutation Taster		=33/167	disease causing

Other links and lift over

dbSNP: rs199476121; hg19: chrM-4137;