rs121434474

chrM-12147-G-A

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PP3 PP5_Very_Strong

The ENST00000387441.1(MT-TH):n.10G>A variant causes a non coding transcript exon change. Variant has been reported in ClinVar as Likely pathogenic (★★★).

• Frequency: Mitomap GenBank: Absent
• Consequence: MT-TH ENST00000387441.1 non_coding_transcript_exon
• Scores: Mitotip Pathogenic 19
• Clinical Significance: Likely pathogenic reviewed by expert panel P:4 O:1 MERRF-MELAS-/-Encephalopathy
• Conservation: PhyloP100: 6.27

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]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PM2: No frequency data in Mitomap. Probably very rare.
• PP3: Mitotip and hmtvar scores support pathogenic criterium.
• PP5: Variant M-12147-G-A is Pathogenic according to our data. Variant chrM-12147-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 9610.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRNH	TRNH.1	n.10G>A		non_coding_transcript_exon_variant	1/1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MT-TH	ENST00000387441.1	n.10G>A		non_coding_transcript_exon_variant	1/1
MT-ND4	ENST00000361381.2			downstream_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

MERRF-MELAS-/-Encephalopathy

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:4 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Mitochondrial disease Pathogenic:2

Likely pathogenic, reviewed by expert panel	curation	ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen	Jan 09, 2023	The m.12147G>A variant in MT-TH has been reported in two unrelated probands with features of primary mitochondrial disease. Both individuals were males with symptom onset in late teens to early 20s, developed seizures, and had COX-negative fibers identified on muscle biopsy. One individual also had ragged red fibers, and complex I and IV deficiencies. Additional features seen include sensorineural hearing loss, optic atrophy, ptosis, migraines, ataxia, myoclonus, muscle weakness, hepatic failure consistent with Reye syndrome, lactic acidosis, and hyperCKemia. Heteroplasmy in the affected individuals ranged from 86% in muscle to undetectable in hair (PS4_supporting; PMIDs: 14967777, 15111688). This variant occurred de novo in one individual (absent in blood, urine, hair, and muscle from mother as well as two sisters, two maternal aunts, and two maternal uncles; PM6, PMID: 15111688). The computational predictor MitoTIP suggests this variant is pathogenic (93.5 percentile) and HmtVAR predicts it to be pathogenic score of 1 (PP3). This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). Single fiber testing was performed in muscle fibers from both affected individuals, supporting the functional impact of this variant (PS3_supporting). In one individual, the mean heteroplasmy level in abnormal fibers was 90% ± 2% (n=22) and in normal fibers was 58% ± 6% (n=15; P = 0.007). Furthermore, in ragged red fibers, the mean heteroplasmy level was 94% (PMID: 14967777). In the other individual, the mean heteroplasmy level in COX-deficient fibers was 94.6 ± 1.53% (n = 12) and in COX-positive fibers was 32.5 ± 6.18% (n = 10; p < 0.0001; PMID: 15111688). In summary, this variant meets criteria to be classified as likely pathogenic 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 January 9, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_supporting, PM6, PM2_supporting, PP3, PS3_supporting. -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -

Juvenile myopathy, encephalopathy, lactic acidosis AND stroke Pathogenic:1 Other:1

Pathogenic, 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.12147G>A variant in MT-TH gene is interpreted to be a Pathogenic variant based on the modified ACMG guidelines (unpublished). This variant meets the following evidence codes reported in the guidelines: PS3, PM7, PM8, PM9 -
not provided, no classification provided	literature only	GeneReviews	-	- -

MERRF/MELAS overlap syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 27, 2004

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Mitotip	Pathogenic	19
Hmtvar	Pathogenic	1.0

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs121434474; hg19: chrM-12148;