rs121434473

Positions:

• chrM-12183-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The ENST00000387441.1(MT-TH):​n.46G>A variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Uncertain significance (★★★).

• Frequency: Mitomap GenBank: 𝑓 0.0 (AC: 1)
• Consequence: MT-TH ENST00000387441.1 non_coding_transcript_exon
• Scores: Mitotip Uncertain 16
• Clinical Significance: Uncertain significance reviewed by expert panel P:1 U:1 RP-+-DEAF
• Conservation: PhyloP100: 1.11

Genes affected

MT-TH (HGNC:7487): (mitochondrially encoded tRNA histidine)

TRNH (HGNC:):

MT-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]

MT-TS2 (HGNC:7498): (mitochondrially encoded tRNA serine 2 (AGU/C))

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very low frequency in mitomap database: 0.0
• PP3: Mitotip and hmtvar scores support pathogenic criterium.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRNH	TRNH.1	n.46G>A		non_coding_transcript_exon_variant	1/1
TRNS2	TRNS2.1			upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MT-TH	ENST00000387441.1	n.46G>A		non_coding_transcript_exon_variant	1/1
MT-ND4	ENST00000361381.2			downstream_gene_variant				ENSP00000354961	P1
MT-TS2	ENST00000387449.1			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 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

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 08, 2003

- -

Mitochondrial disease Uncertain:1

Uncertain significance, reviewed by expert panel

curation

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

Mar 26, 2024

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;