20-3215285-TG-T
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Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The ENST00000380113.8(ITPA):βc.270delβ(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 (β ). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: π 0.0000066 ( 0 hom., cov: 33)
Exomes π: 0.0000096 ( 0 hom. )
Consequence
ITPA
ENST00000380113.8 frameshift
ENST00000380113.8 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 | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ITPA | NM_033453.4 | c.270del | p.Trp90CysfsTer6 | frameshift_variant | 5/8 | ENST00000380113.8 | NP_258412.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ITPA | ENST00000380113.8 | c.270del | p.Trp90CysfsTer6 | frameshift_variant | 5/8 | 1 | NM_033453.4 | ENSP00000369456 | 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 | Labcorp Genetics (formerly Invitae), Labcorp | 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