M-3308-T-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 Benign/Likely_benign. ClinVar VariationId 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

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.2T>C	p.Met1?	start_lost	Exon 1 of 1	ENSP00000354687.2
	MT-TL1	ENST00000386347.1	TSL:6	n.*4T>C		downstream_gene	N/A
	MT-RNR2	ENST00000387347.2	TSL:6	n.*79T>C		downstream_gene	N/A

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

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
1	-	-	Carcinoma of colon (1)
-	-	1	Leigh syndrome (1)
1	-	-	SUDDEN INFANT DEATH SYNDROME (1)

Computational scores

Source: dbNSFP v4.9

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;