M-4363-T-C

Variant names:

• chrM-4363-T-C
• rs200009705
• unassigned_transcript_4791:c.38A>G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP6_Very_Strong BS2

Variant has been reported in ClinVar as Likely benign (★★).

• Frequency: Mitomap GenBank: 𝑓 0.00090 (AC: 55)
• Consequence: TRNQ missense
• Scores: Mitotip Benign 3.9
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:2 Metabolic-syndrome-and-polycystic-ovary-syndrome-/-possibly-associated-w-DEAF-+-RP-+-dev-delay-/-hypertension-/-LHON
• Conservation: PhyloP100: -0.938

Genes affected

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

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]

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

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP6: Variant M-4363-T-C is Benign according to our data. Variant chrM-4363-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 235017.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomadMitoHomoplasmic at 72

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRNQ	unassigned_transcript_4791	c.38A>G	p.Asp13Gly	missense_variant	Exon 1 of 1
ND2	unassigned_transcript_4793	c.-107T>C		upstream_gene_variant
TRNM	unassigned_transcript_4792	c.-39T>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: 0.00090 AC: 55

Gnomad homoplasmic AF: 0.0013 AC: 72 AN: 56424

Gnomad heteroplasmic AF: 0.000035 AC: 2 AN: 56424

Alfa AF: 0.00202 Hom.: 70

Mitomap

Metabolic-syndrome-and-polycystic-ovary-syndrome-/-possibly-associated-w-DEAF-+-RP-+-dev-delay-/-hypertension-/-LHON

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Dec 18, 2012

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-TQ m.4363 T>C Given the data reviewed below, we classify this variant as a variant of uncertain significance. This variant has not been reported in association with cardiomyopathy. It has been reported in association with other mitochondrial phenotypes but it has also been seen in controls. Wong et al (2002) reported the variant as homoplasmic in a 7yo girl with retinitis pigmentosa, hearing loss, and failure to thrive. Zhu et al (2009) repoted a decrase in oxygen consumptionm rate in cell lines with this variant. Abu-Amero et al (2008) observed the variant in a patient with psudoexfoliation syndrome and considered the variant not pathobenic. The variant has been seen in a total of 8 out of 12,830 individuals studies. It was observed in 1 of 2704 individuals in mtDB, 2 of 3735 individuals in MitoWheel. -

not provided Benign:1

Jan 04, 2023

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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.4363T>C variant in MT-TQ 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 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Mitotip	Benign	3.9
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: rs200009705; hg19: chrM-4364;