rs121434471

chrM-4291-T-C

Variant summary

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

The ENST00000387365.1(MT-TI):n.29T>C variant causes a non coding transcript exon change. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Mitomap GenBank: 𝑓 0.0 (AC: 0)
• Consequence: MT-TI ENST00000387365.1 non_coding_transcript_exon
• 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

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 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/exons	MANE	UniProt
TRNI	TRNI.1	n.29T>C		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.29T>C		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: 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

Pathogenic, criteria provided, single submitter	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	Jul 07, 2021	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). -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 12, 2004	- -
Pathogenic, no assertion criteria provided	clinical testing	Undiagnosed Diseases Network, NIH	Nov 09, 2022	- -

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;