ENST00000361390.2:c.29T>C

Variant names:

• chrM-3335-T-C
• rs879173824
• ENST00000361390.2:c.29T>C

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4 BP6_Moderate BS2

The ENST00000361390.2(MT-ND1):​c.29T>C​(p.Ile10Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Mitomap GenBank: 𝑓 0.0010 (AC: 61)
• Consequence: MT-ND1 ENST00000361390.2 missense
• Scores: Apogee2 Benign 0.20
• Clinical Significance: Benign criteria provided, single submitter B:1 LHON
• Conservation: PhyloP100: 1.95
• Publications: 2 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]

TRNL1 (HGNC:7490): (mitochondrially encoded tRNA leucine 1 (UUA/G)) Implicated in cardiomyopathy. [provided by Alliance of Genome Resources, Apr 2022]

MT-RNR2 (HGNC:7471): (mitochondrially encoded 16S RNA) Enables G protein-coupled receptor binding activity; protein self-association; and receptor antagonist activity. Involved in several processes, including leukocyte chemotaxis; negative regulation of cell death; and negative regulation of neuroinflammatory response. Located in several cellular components, including mitochondrion; perinuclear region of cytoplasm; and sperm midpiece. [provided by Alliance of Genome Resources, Apr 2022]

MT-RNR2 Gene-Disease associations (from GenCC):

• mitochondrial disease

  Inheritance: Mitochondrial Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -7 ACMG points.

• BP4: Apogee2 supports a benign effect, 0.19750483 < 0.5 .
• BP6: Variant M-3335-T-C is Benign according to our data. Variant chrM-3335-T-C is described in ClinVar as [Benign]. Clinvar id is 692336.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomadMitoHomoplasmic at 78

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ND1	unassigned_transcript_4789	c.29T>C	p.Ile10Thr	missense_variant	Exon 1 of 1
TRNL1	unassigned_transcript_4788	c.*31T>C		downstream_gene_variant
RNR2	unassigned_transcript_4787	n.*106T>C		downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MT-ND1	ENST00000361390.2	c.29T>C	p.Ile10Thr	missense_variant	Exon 1 of 1	6		ENSP00000354687.2
MT-TL1	ENST00000386347.1	n.*31T>C		downstream_gene_variant		6
MT-RNR2	ENST00000387347.2	n.*106T>C		downstream_gene_variant		6

Frequencies

Mitomap GenBank AF: 0.0010 AC: 61

Gnomad homoplasmic AF: 0.0014 AC: 78 AN: 56424

Gnomad heteroplasmic AF: 0.000035 AC: 2 AN: 56424

Alfa AF: 0.00111 Hom.: 5

Mitomap

Disease(s): LHON

Status: Reported

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

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.3335T>C (YP_003024026.1:p.Ile10Thr) 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	Benign	0.20
Hmtvar	Benign	0.19
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.42	T
DEOGEN2	Benign	0.11	T
LIST_S2	Benign	0.60	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		1.9
PROVEAN	Uncertain	-3.9	D
Sift4G	Uncertain	0.022	D
GERP RS		3.5
Varity_R		0.65
Mutation Taster		=100/0	polymorphism

Other links and lift over

dbSNP: rs879173824; hg19: chrM-3336;