M-4277-T-C

Variant names:

• chrM-4277-T-C
• rs876661358
• unassigned_transcript_4790:c.15T>C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP6_Moderate BS2

Variant has been reported in ClinVar as Benign (★).

• Frequency: Mitomap GenBank: 𝑓 0.00030 (AC: 20)
• Consequence: TRNI synonymous
• Scores: Mitotip Benign 3.7
• Clinical Significance: Benign criteria provided, single submitter U:1 B:1 O:1 HCM-/-Poss.-hypertension-factor
• Conservation: PhyloP100: -1.85

Genes affected

TRNI (HGNC:7488): (mitochondrially encoded tRNA isoleucine)

ND2 (HGNC:7456): (mitochondrially encoded NADH dehydrogenase 2) Enables NADH dehydrogenase (ubiquinone) activity. Involved in mitochondrial electron transport, NADH to ubiquinone and mitochondrial respiratory chain complex I assembly. Part of mitochondrial respiratory chain complex I. Implicated in Leber hereditary optic neuropathy; multiple sclerosis; myocardial infarction; neurodegenerative disease (multiple); and urinary bladder cancer. [provided by Alliance of Genome Resources, Apr 2022]

TRNM (HGNC:7492): (mitochondrially encoded tRNA methionine)

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]

TRNQ (HGNC:7495): (mitochondrially encoded tRNA glutamine)

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP6: Variant M-4277-T-C is Benign according to our data. Variant chrM-4277-T-C is described in ClinVar as [Benign]. Clinvar id is 235012.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomadMitoHomoplasmic at 9

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRNI	unassigned_transcript_4790	c.15T>C	p.Asp5Asp	synonymous_variant	Exon 1 of 1
ND2	unassigned_transcript_4793	c.-193T>C		upstream_gene_variant
TRNM	unassigned_transcript_4792	c.-125T>C		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt

Frequencies

GnomAD4 exome Cov.: 0

We have no GnomAD4 genomes data on this position. Probably position not covered by the project.

Mitomap GenBank AF: 0.00030 AC: 20

Gnomad homoplasmic AF: 0.00016 AC: 9 AN: 56430

Gnomad heteroplasmic AF: 0.000018 AC: 1 AN: 56430

Alfa AF: 0.000112 Hom.: 0

Mitomap

HCM-/-Poss.-hypertension-factor

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 09, 2011

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. MT-TI m.4277 T>C Given the lack of conservation in that region and lack of reported case data, (reviewed below) we consider this variant a variant of uncertain significance. This variant has been reported previously in one study examining the relationship between mitochondrial tRNA genes and hypertension, however a functional link between this variant and hypertension was not assessed in this study (Maron B et al., 2002). The 4277 position in the MT-TI gene is not highly conserved across species, with several species harboring a cytosine "C" nucleotide at this position. This variant is located in the DHU-loop of MT-TI and it is not predicted to alter the secondary structure of the tRNA-Gly. The variant has not been observed in various control populations of 2704 to 6391 individuals (Mitomap, mtDB, MItoWheel). -

MELAS syndrome Benign:1

Jul 12, 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.4277T>C variant in MT-TI gene is interpreted to be a Benign variant based on the modified ACMG guidelines (unpublished). This variant meets the following evidence codes reported in the guidelines: BS1, BS4, BP4 -

not provided Other:1

-

GenomeConnect-Association for Creatine Deficiencies, Association for Creatine Deficiencies

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant interpreted as Uncertain significance and reported on 06-08-2017 by GTR ID 1006. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect facilitates ClinVar submission from the Association for Creatine Deficiencies registry and does not attempt to reinterpret the variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Mitotip	Benign	3.7
Hmtvar	Pathogenic	0.65

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs876661358; hg19: chrM-4278;