ENST00000361390.2:c.2T>C

Variant names:

• chrM-3308-T-C
• rs28358582
• ENST00000361390.2:c.2T>C

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 1P and 16B. PVS1_Supporting BP6_Very_Strong BS1 BS2

The ENST00000361390.2(MT-ND1):​c.2T>C​(p.Met1?) variant causes a start lost change. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency: Mitomap GenBank: 𝑓 0.0070 (AC: 426)
• Consequence: MT-ND1 ENST00000361390.2 start_lost
• Scores: Apogee2 Benign 0.33
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:2 B:3 MELAS-/-DEAF-enhancer-/-hypertension-/-LVNC-/-putative-LHON,Sudden-Infant-Death
• Conservation: PhyloP100: 4.72
• Publications: 25 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 -15 ACMG points.

• PVS1: Start lost variant, no pathogenic variants between lost start and next in-frame start position. Next in-frame start position is after 3 codons. Genomic position: 3313. Lost 0.007 part of the original CDS.
• BP6: Variant M-3308-T-C is Benign according to our data. Variant chrM-3308-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 9728.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: High frequency in mitomap database: 0.0069999998
• BS2: High AC in GnomadMitoHomoplasmic at 1609

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ND1	unassigned_transcript_4789	c.2T>C	p.Met1?	start_lost	Exon 1 of 1
TRNL1	unassigned_transcript_4788	c.*4T>C		downstream_gene_variant
RNR2	unassigned_transcript_4787	n.*79T>C		downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MT-ND1	ENST00000361390.2	c.2T>C	p.Met1?	start_lost	Exon 1 of 1	6		ENSP00000354687.2
MT-TL1	ENST00000386347.1	n.*4T>C		downstream_gene_variant		6
MT-RNR2	ENST00000387347.2	n.*79T>C		downstream_gene_variant		6

Frequencies

Mitomap GenBank AF: 0.0070 AC: 426

Gnomad homoplasmic AF: 0.029 AC: 1609 AN: 56409

Gnomad heteroplasmic AF: 0.000089 AC: 5 AN: 56409

Alfa AF: 0.0108 Hom.: 50

Mitomap

Disease(s): MELAS-/-DEAF-enhancer-/-hypertension-/-LVNC-/-putative-LHON,Sudden-Infant-Death

Status: Reported---possibly-synergistic|-hg-L1b-and-A2i-marker,Reported

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:2 Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Feb 04, 2020

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 31, 2015

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Carcinoma of colon Pathogenic:1

Nov 01, 1999

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

SUDDEN INFANT DEATH SYNDROME Pathogenic:1

Nov 01, 1999

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.3308T>C (YP_003024026.1:p.Met1Thr) 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	0.33
Hmtvar	Pathogenic	0.74
BayesDel_addAF	Benign	-0.23	T
PhyloP100		4.7
GERP RS		3.1
Varity_R		0.12
Mutation Taster		=96/104	disease causing

Other links and lift over

dbSNP: rs28358582; hg19: chrM-3309; COSMIC: COSV104421140; COSMIC: COSV104421140;