rs199476121

Positions:

• chrM-4136-A-G

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP3 BP6_Moderate 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 nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency: Mitomap GenBank: 𝑓 0.0012 (AC: 71)
• Consequence: MT-ND1 ENST00000361390.2 missense
• Scores: Apogee2 Pathogenic 0.75
• Clinical Significance: Benign criteria provided, single submitter P:1 B:1 LHON
• Conservation: PhyloP100: 7.06

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]

ACMG classification

Verdict is Likely_benign. Variant got -5 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 id is 9727.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomadMitoHomoplasmic at 35

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MT-ND1	ENST00000361390.2	c.830A>G	p.Tyr277Cys	missense_variant	1/1			P1

Frequencies

GnomAD4 exome Cov.: 0

We have no GnomAD4 genomes data on this position. Probably position not covered by the project.

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

LHON

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1 Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Leber optic atrophy Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 01, 1991

- -

Leigh syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Oct 17, 2019

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 -

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
MutationTaster	Benign	0.000012	A
PROVEAN	Pathogenic	-8.1	D
Sift4G	Uncertain	0.0040	D
GERP RS		4.5
Varity_R		0.89

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs199476121; hg19: chrM-4137;