M-1619-C-T

Position:

• chrM-1619-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4 BP6_Strong

The ENST00000387342.1(MT-TV):​n.18C>T 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: 2)
• Consequence: MT-TV ENST00000387342.1 non_coding_transcript_exon
• Scores: Mitotip Benign 5.4
• Clinical Significance: Uncertain significance reviewed by expert panel U:2 B:1 No linked disesase in Mitomap
• Conservation: PhyloP100: -12.0

Genes affected

MT-TV (HGNC:7500): (mitochondrially encoded tRNA valine)

TRNV (HGNC:):

MT-RNR1 (HGNC:7470): (mitochondrially encoded 12S RNA) Enables DNA binding activity and DNA-binding transcription factor binding activity. Involved in several processes, including osteoblast proliferation; regulation of carbohydrate utilization; and regulation of phosphate metabolic process. Located in extracellular space; mitochondrion; and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PM2: Very low frequency in mitomap database: 0.0
• BP4: Mitotip and hmtvar scores support benign criterium.
• BP6: Variant M-1619-C-T is Benign according to our data. Variant chrM-1619-C-T is described in ClinVar as [Uncertain_significance]. Clinvar id is 618222.Status of the report is reviewed_by_expert_panel, 3 stars. We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRNV	TRNV.1	n.18C>T		non_coding_transcript_exon_variant	1/1
RNR1	RNR1.1			downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MT-TV	ENST00000387342.1	n.18C>T		non_coding_transcript_exon_variant	1/1
MT-RNR1	ENST00000389680.2			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: 2

Gnomad homoplasmic AF: 0.000053 AC: 3 AN: 56434

Gnomad heteroplasmic AF: 0.0 AC: 0 AN: 56434

Mitomap

No disease associated.

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2 Benign:1

Revision: reviewed by expert panel

Submissions by phenotype

Mitochondrial disease Uncertain:1

Uncertain significance, reviewed by expert panel

curation

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

Jun 26, 2023

The m.1619C>T variant in MT-TV has been reported in one individual in the medical literature, however no clinical details are provided (PMID: 31965079). There are no reported de novo occurrences of this variant to our knowledge. There are no reports of large families with this variant segregating with disease manifestations. This variant is present in population databases (Mitomap's 3/59,389 sequences: AF=0.005%; Helix's 24/195,983 sequences: AF=0.055%; and gnomAD v3.1.2: AF=0.005% including three homoplasmic occurrences). The computational predictor MitoTIP suggests this variant is benign (15.2 percentile) and HmtVAR (score 0) predicts it to be polymorphic (BP4). There are no cybrids, single fiber studies, or other functional assays reported on this variant. 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 June 26, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): BP4. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Jul 18, 2017

This variant affects the mitochondrial tRNA for valine and has not been reported in the medical literature, is not listed in gene-specific variant databases, nor has it been previously identified in our laboratory. It is also rare in population databases such as MITOMAP (0.005% population frequency). However, the cytosine at position 1619 is weakly conserved (UCSC genome browser), suggesting this variant is evolutionary tolerated. However, based on the available information, the clinical significance of the m.1619C>T variant cannot be determined with certainty. -

Juvenile myopathy, encephalopathy, lactic acidosis AND stroke Benign:1

Likely benign, 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.1619C>T variant in MT-TV gene is interpreted to be a Likely Benign variant based on the modified ACMG guidelines (unpublished). This variant meets the following evidence codes reported in the guidelines: BS1, BP5, BP4 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Mitotip	Benign	5.4
Hmtvar	Benign	0.0

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1569483811; hg19: chrM-1621;