M-4314-TA-T

Variant names:

• chrM-4314-TA-T
• rs876661361
• unassigned_transcript_4790:c.55delA

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP6_Moderate

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

• Frequency: Mitomap GenBank: 𝑓 0.00030 (AC: 16)
• Consequence: TRNI frameshift
• Scores: Mitotip Benign 2.8
• Clinical Significance: Benign criteria provided, single submitter U:1 B:1 Ptosis+-deafness+-stroke-like-episodes
• Conservation: PhyloP100: 0.570

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 -2 ACMG points.

• BP6: Variant M-4314-TA-T is Benign according to our data. Variant chrM-4314-TA-T is described in ClinVar as [Benign]. Clinvar id is 235015.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRNI	unassigned_transcript_4790	c.55delA	p.Thr19fs	frameshift_variant	Exon 1 of 1
ND2	unassigned_transcript_4793	c.-155delA		upstream_gene_variant
TRNM	unassigned_transcript_4792	c.-87delA		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: 16

Mitomap

Ptosis+-deafness+-stroke-like-episodes

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 05, 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-TI m.4317delA This variant has been reported in an individual with chronic progressive external opthalmoplegia (CPEO). The patient was homoplasmic for the variant in question while harboring two additional mitochondrial variants (Kornblum et al 2008). Two maternal family members were also found to carry m.4317delA in MT-TI gene and were asymptomatic. It is thought that m.4317delA may act as a modifier and likely does not cause disease without other contributing variants. Functional data suggests the deletion reduces t-RNAIle levels in muscle tissue and affects the net charge of the t-RNA molecule (Kornblum et al 2008). The Human Mitochondrial Database reports the presence of this variant in 1 out of 6391 presumably healthy individuals (http://www.mtdb.igp.uu.se/). MitoWheel reports the variant in 2 out of 3735 individuals (http://mitowheel.org/mitowheel.html). -

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.4317delA 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, BP5 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Mitotip	Benign	2.8

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs876661361; hg19: chrM-4315;