chr7-144453621-T-C
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PP3_StrongPP5
The NM_022445.4(TPK1):c.656A>G(p.Asn219Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000991 in 1,613,816 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). Synonymous variant affecting the same amino acid position (i.e. N219N) has been classified as Likely benign.
Frequency
Consequence
NM_022445.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TPK1 | NM_022445.4 | c.656A>G | p.Asn219Ser | missense_variant | 9/9 | ENST00000360057.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TPK1 | ENST00000360057.7 | c.656A>G | p.Asn219Ser | missense_variant | 9/9 | 1 | NM_022445.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152192Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000199 AC: 5AN: 251414Hom.: 0 AF XY: 0.0000294 AC XY: 4AN XY: 135876
GnomAD4 exome AF: 0.00000958 AC: 14AN: 1461624Hom.: 0 Cov.: 30 AF XY: 0.0000110 AC XY: 8AN XY: 727132
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152192Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74354
ClinVar
Submissions by phenotype
Childhood encephalopathy due to thiamine pyrophosphokinase deficiency Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Apr 02, 2020 | This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS4,PM2,PM3,PP2,PP3. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 09, 2011 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | May 16, 2023 | For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects TPK1 function (PMID: 30483896). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TPK1 protein function. ClinVar contains an entry for this variant (Variation ID: 30572). This missense change has been observed in individual(s) with thiamine metabolism dysfunction syndrome (PMID: 22152682, 28747443). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs371271054, gnomAD 0.02%). This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 219 of the TPK1 protein (p.Asn219Ser). - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 17, 2015 | The N219S missense variant in the TPK1 gene has been reported previously in association with thiaminepyrophosphokinase deficiency in a patient who was compound heterozygous for N219S and a frameshiftvariant (Mayr et al. 2011). N219S occurs at a position that is conserved across species, in silico analysispredicts that N219S is probably damaging to the protein structure/function, and a missense variant in anearby residue (D222H) has also been reported in the Human Gene Mutation Database in association withthiamine pyrophosphokinase deficiency (Stenson et al., 2014), supporting the functional importance of thisregion of the protein. Therefore, we interpret N219S to be a pathogenic variant. - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | May 25, 2022 | The c.656A>G (p.N219S) alteration is located in exon 9 (coding exon 8) of the TPK1 gene. This alteration results from a A to G substitution at nucleotide position 656, causing the asparagine (N) at amino acid position 219 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at