rs200086262
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong
The NM_033453.4(ITPA):c.452G>A(p.Trp151*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000322 in 1,613,968 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 Pathogenic (★★).
Frequency
Consequence
NM_033453.4 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ITPA | NM_033453.4 | c.452G>A | p.Trp151* | stop_gained | Exon 7 of 8 | ENST00000380113.8 | NP_258412.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152226Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000557 AC: 14AN: 251172Hom.: 0 AF XY: 0.0000295 AC XY: 4AN XY: 135816
GnomAD4 exome AF: 0.0000342 AC: 50AN: 1461742Hom.: 0 Cov.: 31 AF XY: 0.0000275 AC XY: 20AN XY: 727190
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152226Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74376
ClinVar
Submissions by phenotype
Inosine triphosphatase deficiency Pathogenic:1
This sequence change creates a premature translational stop signal (p.Trp151*) in the ITPA gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 44 amino acid(s) of the ITPA protein. This variant is present in population databases (rs200086262, gnomAD 0.04%). This premature translational stop signal has been observed in individuals with ITPA-related conditions (PMID: 26224535, 30856165). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 218089). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts a region of the ITPA protein in which other variant(s) (p.Arg178Cys) have been observed in individuals with ITPA-related conditions (PMID: 26224535). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Developmental and epileptic encephalopathy, 35 Pathogenic:1
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not provided Pathogenic:1
The W151X variant has been previously reported in the homozygous state in two siblings with progressive microcephaly, seizures, and developmental delay; ITPase activity in erythrocytes of one of the siblings was found to be severely reduced (Kevelam et. al., 2015). The W151X variant is observed in 11/25636 (0.04%) alleles from individuals of Finnish background, in large population cohorts (Lek et al., 2016). This nonsense variant is predicted to cause loss of normal protein function through protein truncation as the last 44 amino acids are lost. Therefore, we interpret W151X as a pathogenic variant. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at