rs121434473

Variant names:

• chrM-12183-G-A
• rs121434473
• unassigned_transcript_4812:c.46G>A

Your query was ambiguous. Multiple possible variants found:

• chrM-12183-G-A
• chrM-12183-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

Variant has been reported in ClinVar as Uncertain significance (★★★).

• Frequency: Mitomap GenBank: 𝑓 0.0 (AC: 1)
• Consequence: TRNH missense
• Scores: Mitotip Uncertain 16
• Clinical Significance: Uncertain significance reviewed by expert panel P:1 U:1 RP-+-DEAF
• Conservation: PhyloP100: 1.11

Genes affected

TRNH (HGNC:7487): (mitochondrially encoded tRNA histidine)

ND5 (HGNC:7461): (mitochondrially encoded NADH dehydrogenase 5) 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; Leigh disease; and MELAS syndrome. [provided by Alliance of Genome Resources, Apr 2022]

TRNL2 (HGNC:7491): (mitochondrially encoded tRNA leucine 2 (CUN))

TRNS2 (HGNC:7498): (mitochondrially encoded tRNA serine 2 (AGU/C))

ND4 (HGNC:7459): (mitochondrially encoded NADH dehydrogenase 4) 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; Parkinson's disease; macular degeneration; and schizophrenia. Biomarker of Alzheimer's disease. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very low frequency in mitomap database: 0.0

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRNH	unassigned_transcript_4812	c.46G>A	p.Glu16Lys	missense_variant	Exon 1 of 1
ND5	unassigned_transcript_4815	c.-154G>A		upstream_gene_variant
TRNL2	unassigned_transcript_4814	c.-83G>A		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt

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: 1

Alfa AF: 0.000112 Hom.: 0

Mitomap

RP-+-DEAF

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Pigmentary retinopathy and sensorineural deafness Pathogenic:1

Apr 08, 2003

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Mitochondrial disease Uncertain:1

Mar 26, 2024

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

Significance: Uncertain significance

Review Status: reviewed by expert panel

Collection Method: curation

The m.12183G>A variant in MT-TH has been reported in one individual with primary mitochondrial disease to date, in a man with myopathy, ataxia, short stature, hypogonadism, retinopathy, cataracts, and sensorineural hearing loss (PMID: 12682337, also included in analysis in PMID: 19718780). The variant was present at 87.2% heteroplasmy in muscle and 38.3% in blood. This man’s sister had sensorineural hearing and pigmentary retinopathy, with the variant present at 21.2% in blood. Their mother with myopathy, cataracts, and hearing loss had the variant present at 12.4% in blood. The variant was undetectable in three healthy maternal aunts and one healthy maternal uncle (PP1_moderate; PMID: 12682337). There are no reported de novo occurrences to our knowledge. There is one occurrence in population databases (GenBank dataset, 1/61,134, an individual in haplogroup L3f; absent in gnomAD v3.1.2 and Helix dataset), however the frequency is still low (PM2_supporting). Single fiber testing showed higher levels of the variant in COX-negative and ragged red fibers (91.4% ± 4.9, n=7) than in COX-positive fibers (58.4% ± 12.8, n=7), p<0.005 (PS3_supporting, PMID: 12682337). The computational predictor MitoTIP suggests this variant is pathogenic (70.3 percentile) and HmtVAR predicts it to be pathogenic score of 0.55 (PP3). 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/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on March 26, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PP1_moderate, PM2_supporting, PS3_supporting, PP3. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Mitotip	Uncertain	16
Hmtvar	Pathogenic	0.55

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs121434473; hg19: chrM-12184;