rs1381781375
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_033453.4(ITPA):c.270del(p.Trp90CysfsTer6) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000093 in 1,613,758 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000096 ( 0 hom. )
Consequence
ITPA
NM_033453.4 frameshift
NM_033453.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 8.04
Genes affected
ITPA (HGNC:6176): (inosine triphosphatase) This gene encodes an inosine triphosphate pyrophosphohydrolase. The encoded protein hydrolyzes inosine triphosphate and deoxyinosine triphosphate to the monophosphate nucleotide and diphosphate. This protein, which is a member of the HAM1 NTPase protein family, is found in the cytoplasm and acts as a homodimer. Defects in the encoded protein can result in inosine triphosphate pyrophosphorylase deficiency which causes an accumulation of ITP in red blood cells. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Jun 2012]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 20-3215285-TG-T is Pathogenic according to our data. Variant chr20-3215285-TG-T is described in ClinVar as [Pathogenic]. Clinvar id is 533413.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ITPA | NM_033453.4 | c.270del | p.Trp90CysfsTer6 | frameshift_variant | 5/8 | ENST00000380113.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ITPA | ENST00000380113.8 | c.270del | p.Trp90CysfsTer6 | frameshift_variant | 5/8 | 1 | NM_033453.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152150Hom.: 0 Cov.: 33
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GnomAD4 exome AF: 0.00000958 AC: 14AN: 1461608Hom.: 0 Cov.: 30 AF XY: 0.0000124 AC XY: 9AN XY: 727142
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GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152150Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74314
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Inosine triphosphatase deficiency Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 05, 2017 | This variant is not present in population databases (ExAC no frequency). For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in ITPA are known to be pathogenic (PMID: 26224535). This variant has not been reported in the literature in individuals with ITPA-related disease. This sequence change creates a premature translational stop signal (p.Trp90Cysfs*6) in the ITPA gene. It is expected to result in an absent or disrupted protein product. - |
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at