rs121434468

chrM-4284-G-AchrM-4284-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 6P and 4B. PM2 PP5_Strong BS2

The ENST00000387365.1(MT-TI):n.22G>A variant causes a non coding transcript exon 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: 2)
• Consequence: MT-TI ENST00000387365.1 non_coding_transcript_exon
• Scores: Mitotip Uncertain 11
• Clinical Significance: Uncertain significance reviewed by expert panel P:3 U:2 Varied-familial-presentation-/-spastic-paraparesis
• Conservation: PhyloP100: -0.759

Genes affected

MT-TI (HGNC:7488): (mitochondrially encoded tRNA isoleucine)

TRNI (HGNC:):

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-TQ (HGNC:7495): (mitochondrially encoded tRNA glutamine)

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very low frequency in mitomap database: 0.0
• PP5: Variant M-4284-G-A is Pathogenic according to our data. Variant chrM-4284-G-A is described in ClinVar as [Uncertain_significance]. Clinvar id is 9604.Status of the report is reviewed_by_expert_panel, 3 stars. We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Pathogenic=1, Likely_pathogenic=1}.
• BS2: High AC in GnomadMitoHomoplasmic at 4

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRNI	TRNI.1	n.22G>A		non_coding_transcript_exon_variant	1/1
TRNQ	TRNQ.1			downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MT-TI	ENST00000387365.1	n.22G>A		non_coding_transcript_exon_variant	1/1
MT-ND1	ENST00000361390.2			downstream_gene_variant				P1
MT-TQ	ENST00000387372.1			downstream_gene_variant

Frequencies

GnomAD4 exome Cov.: 0

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

Mitomap GenBank AF: 0.0 AC: 2

Gnomad homoplasmic AF: 0.000071 AC: 4 AN: 56426

Gnomad heteroplasmic AF: 0.000035 AC: 2 AN: 56426

Mitomap

Varied-familial-presentation-/-spastic-paraparesis

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:3 Uncertain:2

Revision: reviewed by expert panel

Submissions by phenotype

MERRF syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Mendelics

May 04, 2022

- -

Juvenile myopathy, encephalopathy, lactic acidosis AND stroke Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

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

Jul 12, 2019

The NC_012920.1:m.4284G>A variant in MT-TI gene is interpreted to be a Likely Pathogenic variant based on the modified ACMG guidelines (unpublished). This variant meets the following evidence codes reported in the guidelines: PM8, PM9, PM10 -

Multisystem disorder Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 2002

- -

Mitochondrial disease Uncertain:1

Uncertain significance, reviewed by expert panel

curation

ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen

Nov 28, 2023

The m.4284G>A variant in MT-TI has been reported in one family to date (PMID: 11782991). The proband had isolated spastic paraparesis and normal muscle biopsy including normal respiratory chain enzyme activities. The variant was present at 55% muscle, 50% in hair, 40% in urine, 30% in skin, 20% in buccal, and 20% in blood. His mother had truncal ataxia, dysarthria, severe hearing loss, mental regression, ptosis, ophthalmoparesis, and diabetes. Her brain MRI showed cortical and subcortical diffuse atrophy and muscle biopsy showed reduced activities of complex I and complex IV. The variant was present at 80% in muscle, 20% in urine, and 30% in blood. The proband had one brother with a multisystem progressive disorder who ultimately died of cardiomyopathy. His brain imaging showed marked cortical and subcortical atrophy. His muscle biopsy showed reductions in complex I, complex IV, and complex V. The variant was present at 90% in muscle. As this is the only family reported to date, PS4 could not be applied. The proband had another brother who was healthy and had undetectable levels of the variant in blood and urine. Therefore, this variant segregated with disease in multiple affected family members and a healthy family member had undetectable levels of the variant (PP1; PMID: 11782991). In silico predictions are inconsistent as MitoTIP suggests this variant is benign (35th percentile) and HmtVAR predicts it to be deleterious (0.55). This variant is present in population databases (Mitomap's 61,168 sequences: AF=0.003%; Helix's 195,983 sequences: AF=0.001%; and gnomAD v3.1.2: AF=0.007% as this is homoplasmic in four individuals and heteroplasmic in two individual). Given the frequency of this variant, it does not meet PM2 criterion. Cybrid studies showed that the homoplasmic mutant clones had decreases in COX activity and oxygen consumption rates compared to controls (PS3_supporting, PMID: 11782991). In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on November 28, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PP1, PS3_supporting. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

New York Genome Center

May 07, 2021

The variant has 0.000106 frequency in the gnomAD(v3) database (56,426 total allele number, 4 homoplasmic alleles, 2 heteroplasmic alleles). The m.4284G>A variant has been reported as likely pathogenic in ClinVar [variation ID: 9604, variant also described in PMID:31965079]. Given the low level of heteroplasmy in detected here, the lack of information on heteroplasmy levels of this variant in different tissues of this proband and its inheritance from a reportedly unaffected mother, the m.4284G>A variant identified in the mitochondrial genome is reported as a variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Mitotip	Uncertain	11
Hmtvar	Pathogenic	0.55

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs121434468; hg19: chrM-4285; COSMIC: COSV62293648;