rs587776436

Variant names:

• chrM-5558-A-G
• rs370471013
• unassigned_transcript_4794:c.47A>G

Variant summary

Our verdict is Uncertain significance. The variant received -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: TRNW unassigned_transcript_4794 stop_lost
• 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
• Publications: 1 publications found

Genes affected

TRNW (HGNC:7501): (mitochondrially encoded tRNA tryptophan)

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]

TRNN (HGNC:7493): (mitochondrially encoded tRNA asparagine)

TRNA (HGNC:7475): (mitochondrially encoded tRNA alanine)

TRNC (HGNC:7477): (mitochondrially encoded tRNA cysteine)

TRNC Gene-Disease associations (from GenCC):

• mitochondrial disease

  Inheritance: Mitochondrial Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received -1 ACMG points.

• BP4: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000387382.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
There are no transcript annotations for this variant.

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MT-TW	ENST00000387382.1	TSL:6	n.47A>G		non_coding_transcript_exon	Exon 1 of 1
	MT-ND2	ENST00000361453.3	TSL:6	c.*47A>G		downstream_gene	N/A	ENSP00000355046.4	P03891
	MT-TA	ENST00000387392.1	TSL:6	n.*29T>C		downstream_gene	N/A

Frequencies

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: 0.00247 Hom.: 27

Mitomap

Disease(s): Reported-in-tic-disorder-patient-/-NSSNHL

Status: Reported-[VUS]

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	1	MELAS syndrome (1)
-	1	-	Mitochondrial disease (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
Mitotip	Uncertain	10
Hmtvar	Benign	0.050
PhyloP100		3.3
Mutation Taster		=100/0	polymorphism

Other links and lift over

dbSNP: rs370471013; hg19: chrM-5559;