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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ND1	unassigned_transcript_4789	c.830A>G	p.Tyr277Cys	missense_variant	Exon 1 of 1
TRNI	unassigned_transcript_4790	c.-127A>G		upstream_gene_variant
TRNQ	unassigned_transcript_4791	c.*193T>C		downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MT-ND1	ENST00000361390.2	c.830A>G	p.Tyr277Cys	missense_variant	Exon 1 of 1	6		ENSP00000354687.2
MT-TI	ENST00000387365.1	n.-127A>G		upstream_gene_variant		6
MT-TQ	ENST00000387372.1	n.*193T>C		downstream_gene_variant		6

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

Significance: Benign

Submissions summary: Pathogenic:1 Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Leber optic atrophy Pathogenic:1

Nov 01, 1991

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Leigh syndrome Benign:1

Oct 17, 2019

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The NC_012920.1:m.4136A>G (YP_003024026.1:p.Tyr277Cys) variant in MTND1 gene is interpretated to be a Benign variant based on the modified ACMG guidelines (unpublished). This variant meets the following evidence codes: BS1, BS2

not provided Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.3

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;