rs1026474882
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong
The NM_000270.4(PNP):c.286-18G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000329 in 1,612,616 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_000270.4 intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000658 AC: 1AN: 152056Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000362 AC: 9AN: 248566Hom.: 0 AF XY: 0.0000372 AC XY: 5AN XY: 134526
GnomAD4 exome AF: 0.0000356 AC: 52AN: 1460560Hom.: 0 Cov.: 32 AF XY: 0.0000317 AC XY: 23AN XY: 726450
GnomAD4 genome AF: 0.00000658 AC: 1AN: 152056Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74272
ClinVar
Submissions by phenotype
Purine-nucleoside phosphorylase deficiency Pathogenic:4
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This sequence change falls in intron 3 of the PNP gene. It does not directly change the encoded amino acid sequence of the PNP protein. This variant is present in population databases (no rsID available, gnomAD 0.006%). This variant has been observed in individual(s) with purine nucleoside phosphorylase deficiency (PMID: 9067751, 24767876; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 505116). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -
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The c.286-18G>A variant in PNP has been reported in 2 patients with purine nucle oside phosphorylase deficiency (in the homozygous and compound heterozygous stat e) (la Marca 2014, Markert 1997) and was demonstrated to cause altered splicing leading to a frameshift in patient cells (Markert 1997). This variant was also i dentified in 3/104,620 of chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org). Although this variant has been seen in the gen eral population, its frequency is low enough to be consistent with a recessive c arrier frequency. In summary, although additional studies are needed to clarify its significance, this variant is likely pathogenic. -
Severe combined immunodeficiency disease Pathogenic:1
Variant summary: PNP c.286-18G>A alters a non-conserved nucleotide located at a position not widely known to affect splicing. However, several computational tools predict a significant impact on normal splicing: Three predict the variant weakens a canonical 3' splicing acceptor site, and four predict the variant creates a cryptic 3' acceptor site 16 bp upstream of the canonical site. At least one publication reports experimental evidence that this variant affects mRNA splicing, resulting in a 16 bp insertion expected to result in a frameshift (Markert_1997). The variant allele was found at a frequency of 3.6e-05 in 248566 control chromosomes (gnomAD). c.286-18G>A has been reported in the literature in multiple individuals affected with Combined Immunodeficiency (Markert_1997, Somech_2013, la Marca_2014, Vignesh_2021), and one patient was compound heterozygous with another pathogenic variant. A homozygous case showed no detectible PNP activity, while their heterozygous parents showed roughly half of normal activity (Somech_2013). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 9067751, 24767876, 23371835, 33628209). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at