M-4454-T-C

Position:

• chrM-4454-T-C

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4 BP6_Moderate BS2

The ENST00000387377.1(MT-TM):​n.53T>C variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (★).

• Frequency: Mitomap GenBank: 𝑓 0.0037 (AC: 224)
• Consequence: MT-TM ENST00000387377.1 non_coding_transcript_exon
• Scores: Mitotip Benign 1.2
• Clinical Significance: Benign criteria provided, single submitter B:1 Possible-contributor-to-mito-dysfunction-/-hypertension
• Conservation: PhyloP100: -0.394

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]

ACMG classification

Verdict is Benign. Variant got -7 ACMG points.

• BP4: Mitotip and hmtvar scores support benign criterium.
• BP6: Variant M-4454-T-C is Benign according to our data. Variant chrM-4454-T-C is described in ClinVar as [Benign]. Clinvar id is 689916.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomadMitoHomoplasmic at 135

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRNM	TRNM.1	n.53T>C		non_coding_transcript_exon_variant	1/1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MT-TM	ENST00000387377.1	n.53T>C		non_coding_transcript_exon_variant	1/1
MT-ND2	ENST00000361453.3			upstream_gene_variant				P1

Frequencies

GnomAD4 exome Cov.: 0

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

Mitomap GenBank AF: 0.0037 AC: 224

Gnomad homoplasmic AF: 0.0024 AC: 135 AN: 56427

Gnomad heteroplasmic AF: 0.000035 AC: 2 AN: 56427

Alfa AF: 0.00134 Hom.: 6

Mitomap

Possible-contributor-to-mito-dysfunction-/-hypertension

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Benign, 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.4454T>C variant in MT-TM 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, BS2, BP4 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Mitotip	Benign	1.2
Hmtvar	Benign	0.20

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs11510098; hg19: chrM-4455;