12-57782802-A-G
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PVS1_SupportingPM2PP5
The NM_005726.6(TSFM):āc.1A>Gā(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.0000239 in 1,590,186 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_005726.6 start_lost
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
TSFM | NM_005726.6 | c.1A>G | p.Met1? | start_lost | Exon 1 of 6 | ENST00000652027.2 | NP_005717.3 | |
TSFM | NM_001172696.2 | c.1A>G | p.Met1? | start_lost | Exon 1 of 7 | NP_001166167.1 | ||
TSFM | NM_001172697.2 | c.1A>G | p.Met1? | start_lost | Exon 1 of 6 | NP_001166168.1 | ||
TSFM | NM_001172695.2 | c.1A>G | p.Met1? | start_lost | Exon 1 of 5 | NP_001166166.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152102Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000937 AC: 2AN: 213516Hom.: 0 AF XY: 0.00000869 AC XY: 1AN XY: 115052
GnomAD4 exome AF: 0.0000236 AC: 34AN: 1438084Hom.: 0 Cov.: 30 AF XY: 0.0000238 AC XY: 17AN XY: 713138
GnomAD4 genome AF: 0.0000263 AC: 4AN: 152102Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74300
ClinVar
Submissions by phenotype
not provided Pathogenic:1Uncertain:1
Observed with a second TSFM variant in a patient with features of a mitochondrial disease, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes (PMID: 32980267); Not observed at significant frequency in large population cohorts (gnomAD); Initiation codon variant in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 23174091, 32980267) -
This sequence change affects the initiator methionine of the TSFM mRNA. The next in-frame methionine is located at codon 51. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with TSFM-related conditions. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at