14-20476432-G-C
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong
The NM_000270.4(PNP):āc.701G>Cā(p.Arg234Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000167 in 1,614,088 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 Likely pathogenic (ā ā ).
Frequency
Consequence
NM_000270.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000657 AC: 10AN: 152210Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000795 AC: 20AN: 251482Hom.: 0 AF XY: 0.0000662 AC XY: 9AN XY: 135916
GnomAD4 exome AF: 0.000177 AC: 259AN: 1461878Hom.: 0 Cov.: 31 AF XY: 0.000176 AC XY: 128AN XY: 727240
GnomAD4 genome AF: 0.0000657 AC: 10AN: 152210Hom.: 0 Cov.: 32 AF XY: 0.0000672 AC XY: 5AN XY: 74358
ClinVar
Submissions by phenotype
Purine-nucleoside phosphorylase deficiency Pathogenic:4
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This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 234 of the PNP protein (p.Arg234Pro). This variant is present in population databases (rs104894451, gnomAD 0.01%). This missense change has been observed in individuals with purine nucleoside phosphorylase deficiency, all of whom also carried a second rare variant in the PNP gene (PMID: 1384322, 9067751, 22132981). ClinVar contains an entry for this variant (Variation ID: 13991). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt PNP protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects PNP function (PMID: 1384322). For these reasons, this variant has been classified as Pathogenic. -
The c.702G>C (p.Arg234Pro) missense variant has been reported in three studies in which it was found in a total of five individuals with purine nucleoside phosphorylase (PNP) deficiency, including in four individuals in a compound heterozygous state and in one individual in a heterozygous state in whom a second variant identified was not identified (Aust et al. 1992; Markert et al. 1997; Walker et al. 2011). Control data are unavailable for this variant, which is reported at a frequency of 0.00002 in the European (non-Finnish) population of the Exome Aggregation Consortium. Transfection of the variant protein into COS cells demonstrated that the variant resulted in no detectable PNP activity (Aust et al. 1992). Based on the evidence, the p.Arg234Pro variant is classified as pathogenic for purine nucleoside phosphorylase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
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Severe combined immunodeficiency disease Pathogenic:1
Variant summary: PNP c.701G>C (p.Arg234Pro) results in a non-conservative amino acid change located in the Nucleoside phosphorylase domain (IPR000845) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-05 in 251482 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in PNP causing Severe Combined Immunodeficiency (8e-05 vs 0.00035), allowing no conclusion about variant significance. c.701G>C has been reported in the literature as a biallelic genotype in individuals affected with Purine nucleoside phosphorylase deficiency (Aust_1992, Markert_1997, Walker_2011). These data indicate that the variant is likely to be associated with disease. The variant protein showed no enzymatic activity when transfected into COS cells, matching levels seen with anti-sense transfected negative controls (Aust_1992). Four ClinVar submitters have assessed the variant since 2014: two classified the variant as likely pathogenic, and two as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
not provided Pathogenic:1
Has been reported previously in association with PNP deficiency in unrelated individuals who harbored the R234P variant and second variant in this gene, although it is not clear whether phase was confirmed in some cases (PMID: 9067751, 1384322, 22132981); Published functional studies demonstrate that cells transfected with this variant have no detectable PNP enzymatic activity (PMID: 1384322); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31589614, 35641516, 9067751, 1384322, 22132981, 34711244) -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at