rs1026474882
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong
The ENST00000361505.10(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
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000036 ( 0 hom. )
Consequence
PNP
ENST00000361505.10 intron
ENST00000361505.10 intron
Scores
2
Clinical Significance
Conservation
PhyloP100: 0.00200
Genes affected
PNP (HGNC:7892): (purine nucleoside phosphorylase) This gene encodes an enzyme which reversibly catalyzes the phosphorolysis of purine nucleosides. The enzyme is trimeric, containing three identical subunits. Mutations which result in nucleoside phosphorylase deficiency result in defective T-cell (cell-mediated) immunity but can also affect B-cell immunity and antibody responses. Neurologic disorders may also be apparent in patients with immune defects. A known polymorphism at aa position 51 that does not affect enzyme activity has been described. A pseudogene has been identified on chromosome 2. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 10 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 14-20474755-G-A is Pathogenic according to our data. Variant chr14-20474755-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 505116.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| PNP | NM_000270.4 | c.286-18G>A | intron_variant | ENST00000361505.10 | NP_000261.2 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| PNP | ENST00000361505.10 | c.286-18G>A | intron_variant | 1 | NM_000270.4 | ENSP00000354532 | P1 | |||
| ENST00000554678.1 | downstream_gene_variant | 5 |
Frequencies
GnomAD3 genomes 0.00000658 AC: 1AN: 152056Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000362 AC: 9AN: 248566Hom.: 0 AF XY: 0.0000372 AC XY: 5AN XY: 134526
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GnomAD4 exome AF: 0.0000356 AC: 52AN: 1460560Hom.: 0 Cov.: 32 AF XY: 0.0000317 AC XY: 23AN XY: 726450
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GnomAD4 genome 0.00000658 AC: 1AN: 152056Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74272
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Purine-nucleoside phosphorylase deficiency Pathogenic:4
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Dec 13, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Feb 05, 2022 | 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). Studies have shown that this variant is associated with altered splicing, but the impact on the resulting protein product is unknown (PMID: 9067751). For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jul 07, 2016 | 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
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 16, 2023 | 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:
Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
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Calibrated prediction
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SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_AG_spliceai
Position offset: 2
DS_AL_spliceai
Position offset: 18
Find out detailed SpliceAI scores and Pangolin per-transcript scores at