rs199474664

Variant names:

• chrM-3250-T-C
• rs199474664
• unassigned_transcript_4788:c.21T>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP7

The ENST00000000000(TRNL1):​c.21T>C​(p.Gly7Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Mitomap GenBank: 𝑓 0.0 (AC: 0)
• Consequence: TRNL1 ENST00000000000 synonymous
• Scores: Mitotip Uncertain 10
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1 MM-/-CPEO-/-cardiomyopathy
• Conservation: PhyloP100: -0.265
• Publications: 3 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 1 ACMG points.

• PM2: Very low frequency in mitomap database: 0.0
• BP7: Synonymous conserved (PhyloP=-0.265 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRNL1	unassigned_transcript_4788	c.21T>C	p.Gly7Gly	synonymous_variant	Exon 1 of 1
ND1	unassigned_transcript_4789	c.-57T>C		upstream_gene_variant
RNR2	unassigned_transcript_4787	n.*21T>C		downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MT-TL1	ENST00000386347.1	n.21T>C		non_coding_transcript_exon_variant	Exon 1 of 1	6
MT-ND1	ENST00000361390.2	c.-57T>C		upstream_gene_variant		6		ENSP00000354687.2
MT-RNR2	ENST00000387347.2	n.*21T>C		downstream_gene_variant		6

Frequencies

Mitomap GenBank AF: 0.0 AC: 0

Gnomad homoplasmic AF: 0.0 AC: 0 AN: 56429

Gnomad heteroplasmic AF: 0.000053 AC: 3 AN: 56429

Alfa AF: 0.00 Hom.: 0

Mitomap

Disease(s): MM-/-CPEO-/-cardiomyopathy

Status: Reported

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Mitochondrial skeletal myopathy, responsive to riboflavin Pathogenic:1

Jan 01, 1997

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

MELAS syndrome Uncertain:1

Jul 12, 2019

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The NC_012920.1:m.3250T>C variant in MT-TL1 gene is interpreted to be a Unknown Significance variant based on the modified ACMG guidelines (unpublished). This variant meets the following evidence codes reported in the guidelines: PM8, PP6, BS4

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Mitotip	Uncertain	10
Hmtvar	Pathogenic	0.50
PhyloP100		-0.27

Other links and lift over

dbSNP: rs199474664; hg19: chrM-3251;