M-4437-C-T

Position:

• chrM-4437-C-T

Variant summary

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

The ENST00000387377.1(MT-TM):​n.36C>T variant causes a non coding transcript exon change involving the alteration of a conserved nucleotide. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Mitomap GenBank: Absent
• Consequence: MT-TM ENST00000387377.1 non_coding_transcript_exon
• Scores: Mitotip Uncertain 15
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1 Hypotonia+-seizure+-muscle-weakness+-lactic-acidosis+-hearing-loss
• Conservation: PhyloP100: 7.53

Genes affected

MT-TM (HGNC:7492): (mitochondrially encoded tRNA methionine)

TRNM (HGNC:):

MT-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]

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

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: No frequency data in Mitomap. Probably very rare.
• PP5: Variant M-4437-C-T is Pathogenic according to our data. Variant chrM-4437-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 689913.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRNM	TRNM.1	n.36C>T		non_coding_transcript_exon_variant	1/1
TRNQ	TRNQ.1			upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MT-TM	ENST00000387377.1	n.36C>T		non_coding_transcript_exon_variant	1/1
MT-ND2	ENST00000361453.3			upstream_gene_variant				P1
MT-TQ	ENST00000387372.1			upstream_gene_variant

Frequencies

GnomAD4 exome Cov.: 0

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

Mitomap

Hypotonia+-seizure+-muscle-weakness+-lactic-acidosis+-hearing-loss

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

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.4437C>T variant in MT-TM 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: PM2, PM9, PM10, PP3, PP6 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Mitotip	Uncertain	15
Hmtvar	Benign	0.30

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1603219459; hg19: chrM-4438;