rs587776436

Positions:

• chrM-5558-A-G

Variant summary

Our verdict is Uncertain significance. Variant got -1 ACMG points: 0P and 1B. BP4

This summary comes from the ClinGen Evidence Repository: The m.5558A>G variant in MT-TW was reviewed by the Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel as part of the variant pilot for mitochondrial DNA variant specifications (McCormick et al., 2020; PMID:32906214). There have been no affected individuals reported in the medical literature to our knowledge. There are no large families reported in the medical literature to consider for evidence of segregation. There are over 100 occurrences in MITOMAP for an overall allele frequency of 0.2%. This does not meet criteria for BA1 or BS1. The computational predictor MitoTIP suggests this variant is possibly benign (31st percentile) and HmtVAR predicts it to be likely polymorphic (0.5, BP4). There are no cybrid or single fiber studies reported on this variant. 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 U24 Mitochondrial Disease Variant Curation Expert Panel as of August 20, 2020. Mitochondrial DNA-specific ACMG/AMP criteria applied: BP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA414780655/MONDO:0044970/014

• Frequency: Mitomap GenBank: 𝑓 0.0019 (AC: 119)
• Consequence: MT-TW ENST00000387382.1 non_coding_transcript_exon
• Scores: Mitotip Uncertain 10
• Clinical Significance: Uncertain significance reviewed by expert panel U:1 B:1 Reported-in-tic-disorder-patient-/-NSSNHL
• Conservation: PhyloP100: 3.29

Genes affected

MT-TW (HGNC:7501): (mitochondrially encoded tRNA tryptophan)

TRNW (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-TA (HGNC:7475): (mitochondrially encoded tRNA alanine)

ACMG classification

Verdict is Uncertain_significance. Variant got -1 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRNW	TRNW.1	n.47A>G		non_coding_transcript_exon_variant	1/1
TRNA	TRNA.1			downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MT-TW	ENST00000387382.1	n.47A>G		non_coding_transcript_exon_variant	1/1
MT-ND2	ENST00000361453.3			downstream_gene_variant				P1
MT-TA	ENST00000387392.1			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: 0.0019 AC: 119

Gnomad homoplasmic AF: 0.0024 AC: 134 AN: 56429

Gnomad heteroplasmic AF: 0.000071 AC: 4 AN: 56429

Alfa AF: 0.000892 Hom.: 4

Mitomap

Reported-in-tic-disorder-patient-/-NSSNHL

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1 Benign:1

Revision: reviewed by expert panel

Submissions by phenotype

Mitochondrial disease Uncertain:1

Uncertain significance, reviewed by expert panel

curation

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

Dec 10, 2021

The m.5558A>G variant in MT-TW was reviewed by the Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel as part of the variant pilot for mitochondrial DNA variant specifications (McCormick et al., 2020; PMID: 32906214). There have been no affected individuals reported in the medical literature to our knowledge. There are no large families reported in the medical literature to consider for evidence of segregation. There are over 100 occurrences in MITOMAP for an overall allele frequency of 0.2%. This does not meet criteria for BA1 or BS1. The computational predictor MitoTIP suggests this variant is possibly benign (31st percentile) and HmtVAR predicts it to be likely polymorphic (0.5, BP4). There are no cybrid or single fiber studies reported on this variant. 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 U24 Mitochondrial Disease Variant Curation Expert Panel as of August 20, 2020. Mitochondrial DNA-specific ACMG/AMP criteria applied: BP4. -

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.5558A>G variant in MT-TW 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, BP5 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Mitotip	Uncertain	10
Hmtvar	Benign	0.050

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs370471013; hg19: chrM-5559;