rs876657868

Variant names:

• chrM-7502-C-T
• rs876657868
• unassigned_transcript_4800:c.13G>A

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.7502C>T variant in MT-TS1 was reviewed by the Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel on July 24, 2023. There are no individuals or families with primary mitochondrial disease with this variant reported in the medical literature to our knowledge. This variant has been reported in one individual in the medical literature, in an individual of Han Chinese descent with a tic disorder (PMID:33289513). Other features were not reported and other genetic etiologies were not assessed. There are several occurrences in population databases. This variant is present in 0.007% of individuals in GenBank MITOMAP sequences, in 0.009% of individuals in gnomAD v3.1.2 (homoplasmic in all five individuals), and in 0.004% of individuals in the Helix dataset (six homoplasmic occurrences, one heteroplasmic). MitoTIP suggests this variant is benign (8.2 percentile) and HmtVAR predicts it to be polymorphic (0.1; BP4). There are no cybrid, single fiber, or other studies reported for 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 July 24, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID:32906214): BP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10577185/MONDO:0044970/015

• Frequency: Mitomap GenBank: 𝑓 0.00010 (AC: 4)
• Consequence: TRNS1 unassigned_transcript_4800 missense
• Scores: Mitotip Benign 3.5
• Clinical Significance: Uncertain significance reviewed by expert panel U:2 B:1 Reported-in-tic-disorder-patient
• Conservation: PhyloP100: -0.689
• Publications: 0 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 -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: 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.13G>A		non_coding_transcript_exon	Exon 1 of 1
	MT-CO2	ENST00000361739.1	TSL:6	c.-84C>T		upstream_gene	N/A	ENSP00000354876.1	P00403
	MT-CO1	ENST00000361624.2	TSL:6	c.*57C>T		downstream_gene	N/A	ENSP00000354499.2	P00395

Frequencies

Mitomap GenBank AF: 0.00010 AC: 4

Gnomad homoplasmic AF: 0.000089 AC: 5 AN: 56433

Gnomad heteroplasmic AF: 0.0 AC: 0 AN: 56433

Mitomap

Disease(s): Reported-in-tic-disorder-patient

Status: Reported-[VUS]

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	Benign	3.5
Hmtvar	Benign	0.10
PhyloP100		-0.69

Other links and lift over

dbSNP: rs876657868; hg19: chrM-7503;