chrM-7465-AC-A

Variant names:

• chrM-7465-AC-A
• rs111033319
• unassigned_transcript_4800:c.49delG

Variant summary

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

This summary comes from the ClinGen Evidence Repository: The m.7471delC variant in MT-TS1 was reviewed by the Mitochondrial Disease Variant Curation Expert Panel on May 22, 2023. This variant has not been reported in the medical literature as causative in affected individuals or families with primary mitochondrial disease to our knowledge. This variant is present in population databases (Mitomap's 28/59,389 sequences: AF= 0.047%; Helix's 162/195,983 sequences: AF=0.070% including 137 homoplasmic occurrences in addition to 25 heteroplasmic occurrences, and in haplogroups H, U, T, K, B, D, M, HV, J, A, I, X, T, C, K, M, W, V; and gnomAD v3.1.2: AF=0.053 % including 30 homoplasmic occurrences in addition to five heteroplasmic occurrences). Given the frequency of this variant, it does not meet PM2 criterion. The computational predictor MitoTIP suggests this variant is benign (4.3 percentile) and HmtVAR does not provide a prediction. Given the lack of computational evidence, BP4 cannot be applied. 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. We note that three experts on this panel felt likely benign was a more appropriate classification given the presence in the general population however the majority (four) agreed with uncertain significance. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on May 22, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID:32906214): None. LINK:https://erepo.genome.network/evrepo/ui/classification/CA131012/MONDO:0044970/015

• Frequency: Mitomap GenBank: 𝑓 0.00050 (AC: 30)
• Consequence: TRNS1 unassigned_transcript_4800 frameshift
• Scores: Mitotip Uncertain 13
• Clinical Significance: Uncertain significance reviewed by expert panel U:2 B:1 Maternally-inherited-hypertension-/-deafness
• Conservation: PhyloP100: 3.93
• Publications: 4 publications found

Genes affected

TRNS1 (HGNC:7497): (mitochondrially encoded tRNA serine 1 (UCN))

MT-CO2 (HGNC:7421): (mitochondrially encoded cytochrome c oxidase II) Contributes to cytochrome-c oxidase activity. Predicted to be involved in mitochondrial electron transport, cytochrome c to oxygen and positive regulation of vasoconstriction. Located in mitochondrial inner membrane. Part of respiratory chain complex IV. Biomarker of Huntington's disease and stomach cancer. [provided by Alliance of Genome Resources, Apr 2022]

MT-CO1 (HGNC:7419): (mitochondrially encoded cytochrome c oxidase I) Contributes to cytochrome-c oxidase activity. Predicted to be involved in electron transport coupled proton transport and mitochondrial electron transport, cytochrome c to oxygen. Part of mitochondrial respiratory chain complex III and mitochondrial respiratory chain complex IV. [provided by Alliance of Genome Resources, Apr 2022]

TRND (HGNC:7478): (mitochondrially encoded tRNA aspartic acid)

TRND Gene-Disease associations (from GenCC):

• mitochondrial disease

  Inheritance: Mitochondrial Classification: MODERATE Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000387416.2. 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-TS1	ENST00000387416.2	TSL:6	n.49delG		non_coding_transcript_exon	Exon 1 of 1
	MT-CO2	ENST00000361739.1	TSL:6	c.-120delC		upstream_gene	N/A	ENSP00000354876.1	P00403
	MT-CO1	ENST00000361624.2	TSL:6	c.*21delC		downstream_gene	N/A	ENSP00000354499.2	P00395

Frequencies

Mitomap GenBank AF: 0.00050 AC: 30

Alfa AF: 0.000786 Hom.: 3

Mitomap

Disease(s): Maternally-inherited-hypertension-/-deafness

Status: Reported-[VUS](=7466d)

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 specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
Mitotip	Uncertain	13
PhyloP100		3.9

Other links and lift over

dbSNP: rs111033319; hg19: chrM-7466;