rs111033319
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
Consequence
unassigned_transcript_4800 frameshift
Scores
Clinical Significance
Conservation
Publications
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ACMG classification
Our verdict: Uncertain_significance. The variant received 0 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| TRNS1 | unassigned_transcript_4800 | c.49delG | p.Val17fs | frameshift_variant | Exon 1 of 1 | |||
| COX2 | unassigned_transcript_4802 | c.-120delC | upstream_gene_variant | |||||
| TRND | unassigned_transcript_4801 | c.-52delC | upstream_gene_variant | |||||
| COX1 | unassigned_transcript_4799 | c.*21delC | downstream_gene_variant |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| MT-TS1 | ENST00000387416.2 | n.49delG | non_coding_transcript_exon_variant | Exon 1 of 1 | 6 | |||||
| MT-CO2 | ENST00000361739.1 | c.-120delC | upstream_gene_variant | 6 | ENSP00000354876.1 | |||||
| MT-CO1 | ENST00000361624.2 | c.*21delC | downstream_gene_variant | 6 | ENSP00000354499.2 | |||||
| MT-TD | ENST00000387419.1 | n.-52delC | upstream_gene_variant | 6 |
Frequencies
Mitomap
ClinVar
Submissions by phenotype
not specified Uncertain:1
The 7471delC variant in MTTS1 has not been reported in the literature nor previo usly identified by our laboratory. However, this deletion of a cytosine (C) nucl eotide occurs within a stretch of 6 cytosine nucleotides and a similar variant ( 7471_7472insC) resulting in an insertion of a cytosine in this same stretch of c ytosine residues has been previously reported in individuals with both nonsyndro mic and syndromic hearing loss (Tiranti 1995, Ensink 1998, Jaksch 1998, Verhoeve n 1999, Hutchin 2001). However, the 7471delC may have a different affect than th e 7471_7472insC variant on the MTTS1 gene. In summary, the clinical significance of this variant cannot be determined with certainty at this time. -
Mitochondrial disease Uncertain:1
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. -
MELAS syndrome Benign:1
The NC_012920.1:m.7471delC variant in MT-TS1 gene is interpreted to be a Benign variant based on the modified ACMG guidelines (unpublished). This variant meets the following evidence codes reported in the guidelines: BS1, BS2, BP4 -
Computational scores
Source: