rs373569964
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate
The NM_000270.4(PNP):c.553C>A(p.Arg185Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,886 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R185H) has been classified as Uncertain significance.
Frequency
Consequence
NM_000270.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.0000199 AC: 5AN: 251454Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135900
GnomAD4 exome AF: 0.00000479 AC: 7AN: 1461886Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2AN XY: 727246
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Purine-nucleoside phosphorylase deficiency Uncertain:1
This sequence change replaces arginine with serine at codon 185 of the PNP protein (p.Arg185Ser). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and serine. This variant is present in population databases (rs373569964, ExAC 0.03%). This variant has not been reported in the literature in individuals affected with PNP-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
not provided Uncertain:1
The R185S variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). R185S is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved in mammals; however, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. In summary, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at