rs1265314976
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PM5PP3_Strong
The NM_022445.4(TPK1):āc.425T>Cā(p.Leu142Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,828 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 Uncertain significance (ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L142F) has been classified as Pathogenic.
Frequency
Consequence
NM_022445.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TPK1 | NM_022445.4 | c.425T>C | p.Leu142Ser | missense_variant | 7/9 | ENST00000360057.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TPK1 | ENST00000360057.7 | c.425T>C | p.Leu142Ser | missense_variant | 7/9 | 1 | NM_022445.4 | P1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251362Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135844
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461828Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1AN XY: 727226
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Childhood encephalopathy due to thiamine pyrophosphokinase deficiency Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Feb 21, 2020 | 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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with TPK1-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces leucine with serine at codon 142 of the TPK1 protein (p.Leu142Ser). The leucine residue is highly conserved and there is a large physicochemical difference between leucine and serine. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at