rs1556424691

Positions:

• chrM-15923-A-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2 PP5_Very_Strong

The ENST00000387460.2(MT-TT):​n.36A>G variant causes a non coding transcript exon change involving the alteration of a conserved nucleotide. Variant has been reported in ClinVar as Likely pathogenic (★★★).

• Frequency: Mitomap GenBank: 𝑓 0.0 (AC: 0)
• Consequence: MT-TT ENST00000387460.2 non_coding_transcript_exon
• Scores: Mitotip Uncertain 12
• Clinical Significance: Likely pathogenic reviewed by expert panel P:2 U:2 LIMM-/-MERRF-/-mito-disease
• Conservation: PhyloP100: 8.59

Genes affected

MT-TT (HGNC:7499): (mitochondrially encoded tRNA threonine)

TRNT (HGNC:):

MT-CYB (HGNC:7427): (mitochondrially encoded cytochrome b) Predicted to enable metal ion binding activity. Predicted to be involved in several processes, including electron transport coupled proton transport; response to cobalamin; and response to glucagon. Located in mitochondrion. Implicated in ovarian carcinoma and urinary bladder cancer. [provided by Alliance of Genome Resources, Apr 2022]

MT-TP (HGNC:7494): (mitochondrially encoded tRNA proline)

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM2: Very low frequency in mitomap database: 0.0
• PP5: Variant M-15923-A-G is Pathogenic according to our data. Variant chrM-15923-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 39575.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRNT	TRNT.1	n.36A>G		non_coding_transcript_exon_variant	1/1
CYTB	CYTB.1			downstream_gene_variant			YP_003024038.1
TRNP	TRNP.1			downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MT-TT	ENST00000387460.2	n.36A>G		non_coding_transcript_exon_variant	1/1
MT-CYB	ENST00000361789.2			downstream_gene_variant				ENSP00000354554	P1
MT-TP	ENST00000387461.2			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: 0.0 AC: 0

Alfa AF: 0.0572 Hom.: 470

Mitomap

LIMM-/-MERRF-/-mito-disease

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2 Uncertain:2

Revision: reviewed by expert panel

Submissions by phenotype

Mitochondrial disease Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Undiagnosed Diseases Network, NIH	Mar 13, 2019	- -
Likely pathogenic, reviewed by expert panel	curation	ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen	Jun 26, 2023	The m.15923A>G variant in MT-TT has been reported in four individuals with primary mitochondrial disease from four unrelated families (PS4_moderate; PMIDs: 1645537, 22638997, 29760464, 30236074). Age of onset varied from the second day of life to the 50s. Affected individuals had features consistent with neonatal lactic acidosis or MERRF (myoclonic epilepsy with ragged red fibers), in addition to myopathy, exercise intolerance, muscle atrophy, ataxia, seizures, migraines, vomiting, sensorineural hearing loss, and pigmentary retinopathy. Heteroplasmy levels in affected individuals ranged from being undetectable in certain tissues to being present at homoplasmy. There was limited testing in family members precluding considering of segregation evidence. There is one report of a de novo occurrence (PMID: 1645537) however the ability to detect low levels of heteroplasmy was limited at the time. There are four heteroplasmic occurrences of this variant in the Helix dataset, and the variant is absent in the GenBank dataset and in gnomAD v3.1.2 (PM2_supporting). MitoTIP suggests this variant is likely benign (46.6 percentile) and HmtVAR predicts it a deleterious effect (0.65). Functional testing demonstrated this variant was associated with impaired tRNA modification (PS3_moderate). This variant meets criteria to be classified as uncertain significance however, after extensive discussion, this Expert Panel elected to modify the classification to likely pathogenic given the consistent phenotypes in affected individuals and strong functional evidence showing impaired modification of the tRNA. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on June 26, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_moderate, PM2_supporting, PS3_moderate. -

Variant of unknown significance Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

OMIM

Aug 01, 1992

- -

Constipation;C0022346:Jaundice;C0085298:Sudden cardiac death;C1848924:Infantile onset;C1855106:Neonatal onset;C1858120:Generalized hypotonia;C2315100:Failure to thrive Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Sep 21, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Mitotip	Uncertain	12
Hmtvar	Pathogenic	0.65

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1556424691; hg19: chrM-15924;