M-3275-C-A

Variant names:

• chrM-3275-C-A
• rs1057516057
• unassigned_transcript_4788:c.46C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP6_Moderate

The ENST00000000000(TRNL1):​c.46C>A​(p.Gln16Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. 3/3 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Mitomap GenBank: 𝑓 0.0 (AC: 3)
• Consequence: TRNL1 ENST00000000000 missense
• Scores: Mitotip Benign 2.0
• Clinical Significance: Likely benign criteria provided, single submitter B:1 LHON,Metabolic-syndrome-and-polycystic-ovary-syndrome-/-LHON
• Conservation: PhyloP100: -3.37
• Publications: 0 publications found

Genes affected

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

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]

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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very low frequency in mitomap database: 0.0
• BP6: Variant M-3275-C-A is Benign according to our data. Variant chrM-3275-C-A is described in ClinVar as Likely_benign. ClinVar VariationId is 689867.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRNL1	unassigned_transcript_4788	c.46C>A	p.Gln16Lys	missense_variant	Exon 1 of 1
ND1	unassigned_transcript_4789	c.-32C>A		upstream_gene_variant
RNR2	unassigned_transcript_4787	n.*46C>A		downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MT-TL1	ENST00000386347.1	n.46C>A		non_coding_transcript_exon_variant	Exon 1 of 1	6
MT-ND1	ENST00000361390.2	c.-32C>A		upstream_gene_variant		6		ENSP00000354687.2
MT-RNR2	ENST00000387347.2	n.*46C>A		downstream_gene_variant		6

Frequencies

Mitomap GenBank AF: 0.0 AC: 3

Gnomad homoplasmic AF: 0.000035 AC: 2 AN: 56433

Gnomad heteroplasmic AF: 0.0 AC: 0 AN: 56433

Mitomap

Disease(s): LHON,Metabolic-syndrome-and-polycystic-ovary-syndrome-/-LHON

Status: Reported,Reported

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

MELAS syndrome Benign:1

Jul 12, 2019

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The NC_012920.1:m.3275C>A variant in MT-TL1 gene is interpreted to be a Likely Benign variant based on the modified ACMG guidelines (unpublished). This variant meets the following evidence codes reported in the guidelines: BS4, BP4 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Mitotip	Benign	2.0
Hmtvar	Benign	0.10
PhyloP100		-3.4

Other links and lift over

dbSNP: rs1057516057; hg19: chrM-3276;