rs199476132

chrM-5728-T-C

Variant summary

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

The ENST00000387400.1(MT-TN):n.2A>G variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely pathogenic (★★★).

• Frequency: Mitomap GenBank: Absent
• Consequence: MT-TN ENST00000387400.1 non_coding_transcript_exon
• Scores: Mitotip Uncertain 16
• Clinical Significance: Likely pathogenic reviewed by expert panel P:5 Multiorgan-failure-/-myopathy
• Conservation: PhyloP100: 1.98

Genes affected

MT-TN (HGNC:7493): (mitochondrially encoded tRNA asparagine)

TRNN (HGNC:):

MT-TC (HGNC:7477): (mitochondrially encoded tRNA cysteine)

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-5728-T-C is Pathogenic according to our data. Variant chrM-5728-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 9622.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRNN	TRNN.1	n.2A>G		non_coding_transcript_exon_variant	1/1
TRNC	TRNC.1			downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MT-TN	ENST00000387400.1	n.2A>G		non_coding_transcript_exon_variant	1/1
MT-TC	ENST00000387405.1			downstream_gene_variant

Frequencies

GnomAD4 exome Cov.: 0

We have no GnomAD4 genomes data on this position. Probably position not covered by the project.

Gnomad homoplasmic AF: 0.0 AC: 0 AN: 56428

Gnomad heteroplasmic AF: 0.000018 AC: 1 AN: 56428

Mitomap

Multiorgan-failure-/-myopathy

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:5

Revision: reviewed by expert panel

Submissions by phenotype

Mitochondrial complex IV deficiency, nuclear type 1 Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 01, 2006	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -

Mitochondrial disease Pathogenic:1

Likely pathogenic, reviewed by expert panel

curation

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

Feb 13, 2023

The m.5728T>C variant in MT-TN has been reported in three unrelated individuals with primary mitochondrial disease (PS4_supporting). Onset was in infancy or childhood, and features seen in these individuals included myopathy, ataxia, developmental delay, multiorgan failure, ptosis, and ophthalmoplegia. The variant was seen at varying heteroplasmy levels in affected individuals, including undetectable to 50% in blood and 41-97% in muscle (PMIDs: 16908752, 23847141, 31026515). The variant was confirmed to have occurred de novo in one of the reported cases, as the variant was undetectable in the mother’s blood and muscle by next-generation sequencing (PMID: 31026515, PM6). In another case, the variant appeared to have arisen de novo as it was not detected in blood from the healthy mother, two siblings, and maternal grandmother, however technology used at the time would not have detected low levels of the variant and additional tissues were not assessed (PMID: 16908752). No details of family member testing were provided in the third case. There are no other large families reported in the medical literature with this variant to consider for evidence of segregation. There is one occurrence of this variant in GenBank dataset and it is absent in gnomAD v3.1.2 and in the Helix dataset, therefore the overall frequency is still very low (PM2_supporting). The computational predictor MitoTIP suggests this variant is pathogenic, scoring in the 71st percentile and HmtVAR also predicts it to be pathogenic, scoring 0.75 (PP3). Cybrid studies support the functional impact of this variant as a combined defect of complexes I and IV was seen (PS3_supporting; PMID: 6908752). 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 February 13, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_supporting, PS3_supporting, PM2_supporting, PP3, PM6. -

MITOCHONDRIAL COMPLEX I DEFICIENCY, MITOCHONDRIAL TYPE 2 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Aug 01, 2006

- -

Juvenile myopathy, encephalopathy, lactic acidosis AND stroke Pathogenic: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.5728T>C variant in MT-TN 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, PM8, PM9, PP3, PP6 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Mitotip	Uncertain	16
Hmtvar	Pathogenic	0.75

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs199476132; hg19: chrM-5729;