rs121434471

Variant names:

• chrM-4291-T-C
• rs121434471
• unassigned_transcript_4790:c.29T>C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP5_Moderate

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

• Frequency: Mitomap GenBank: 𝑓 0.0 (AC: 0)
• Consequence: TRNI missense
• Scores: Mitotip Uncertain 10
• Clinical Significance: Pathogenic criteria provided, single submitter P:3 Hypomagnesemic-Metabolic-Syndrome-/-Gitelman-like-syndrome
• Conservation: PhyloP100: 5.91

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very low frequency in mitomap database: 0.0
• PP5: Variant M-4291-T-C is Pathogenic according to our data. Variant chrM-4291-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 9607.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.29T>C	p.Leu10Ser	missense_variant	Exon 1 of 1
ND2	unassigned_transcript_4793	c.-179T>C		upstream_gene_variant
TRNM	unassigned_transcript_4792	c.-111T>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: 0.0 AC: 0

Mitomap

Hypomagnesemic-Metabolic-Syndrome-/-Gitelman-like-syndrome

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, single submitter

Submissions by phenotype

Hypomagnesemia, hypertension, and hypercholesterolemia, mitochondrial Pathogenic:3

Jul 07, 2021

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The m.4291T>C variant was observed in 4 families affected by hypomagnesemia with renal magnesium wasting and hypokalemia.(Viering et al. 2021) The (near) homoplasmic variant cosegregated with disease. The variant was scored as pathogenic when using the system published by Wong et al. (2020) as basis: PS2, PS4, PM9, PM10, PP6 (additionally, PP7 and PS5 were previously met in a study by Wilson et al. 2004). -

Nov 12, 2004

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Nov 09, 2022

Undiagnosed Diseases Network, NIH

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Mitotip	Uncertain	10
Hmtvar	Pathogenic	0.40

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs121434471; hg19: chrM-4292;