chr22-50525802-AG-A
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong
The NM_001953.5(TYMP):c.1416delC(p.Phe473SerfsTer16) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000197 in 152,218 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_001953.5 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152218Hom.: 0 Cov.: 35
GnomAD4 exome Cov.: 38
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152218Hom.: 0 Cov.: 35 AF XY: 0.0000403 AC XY: 3AN XY: 74368
ClinVar
Submissions by phenotype
not provided Pathogenic:2
Studies have shown that this frameshift alters TYMP gene expression (PMID: 21412940). ClinVar contains an entry for this variant (Variation ID: 817030). This variant is also known as p.F473SfsX41. This frameshift has been observed in individual(s) with mitochondrial neurogastrointestinal encephalomyopathy (PMID: 21412940). This variant is not present in population databases (gnomAD no frequency). This sequence change results in a frameshift in the TYMP gene (p.Phe473Serfs*?). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 10 amino acid(s) of the TYMP protein and extend the protein by an uncertain number of additional amino acid residues. For these reasons, this variant has been classified as Pathogenic. -
The c.1414delC variant has been reported previously in an individual with mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) who was homozygous for this change (Torres-Torronteras et al., 2011). The c.1414delC variant causes a frameshift starting with codon Phenylalanine 473, changes this amino acid to a Serine residue and is expected to extend the open reading frame to an unknown length, denoted p.Phe473SerfsX?. Other frameshift variants, including one downstream of c.1414delC, have been reported in the Human Gene Mutation Database in individuals with MNGIE (Stenson et al., 2014). Furthermore, the c.1414delC variant is not observed in large population cohorts (Lek et al., 2016). Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded. -
Mitochondrial DNA depletion syndrome 1 Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at