chrM-1619-C-T

Variant names:

• chrM-1619-C-T
• rs1569483811
• unassigned_transcript_4786:c.18C>T

Variant summary

Our verdict is Uncertain significance. The variant received -1 ACMG points: 0P and 1B. BP4

This summary comes from the ClinGen Evidence Repository: 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. LINK:https://erepo.genome.network/evrepo/ui/classification/CA913163215/MONDO:0044970/014

• Frequency: Mitomap GenBank: 𝑓 0.0 (AC: 2)
• Consequence: TRNV unassigned_transcript_4786 synonymous
• 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
• Publications: 0 publications found

Genes affected

TRNV (HGNC:7500): (mitochondrially encoded tRNA valine)

MT-RNR2 (HGNC:7471): (mitochondrially encoded 16S RNA) Enables G protein-coupled receptor binding activity; protein self-association; and receptor antagonist activity. Involved in several processes, including leukocyte chemotaxis; negative regulation of cell death; and negative regulation of neuroinflammatory response. Located in several cellular components, including mitochondrion; perinuclear region of cytoplasm; and sperm midpiece. [provided by Alliance of Genome Resources, Apr 2022]

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]

MT-RNR1 Gene-Disease associations (from GenCC):

• mitochondrial disease

  Inheritance: Mitochondrial Classification: DEFINITIVE Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received -1 ACMG points.

• BP4: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000387342.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
There are no transcript annotations for this variant.

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MT-TV	ENST00000387342.1	TSL:6	n.18C>T		non_coding_transcript_exon	Exon 1 of 1
	MT-RNR2	ENST00000387347.2	TSL:6	n.-52C>T		upstream_gene	N/A
	MT-RNR1	ENST00000389680.2	TSL:6	n.*18C>T		downstream_gene	N/A

Frequencies

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

ClinVar submissions

Significance: Uncertain significance

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	1	MELAS syndrome (1)
-	1	-	Mitochondrial disease (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
Mitotip	Benign	5.4
Hmtvar	Benign	0.0
PhyloP100		-12

Other links and lift over

dbSNP: rs1569483811; hg19: chrM-1621;