14-20476432-G-C

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong

The NM_000270.4(PNP):c.701G>C(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 (★★).

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00018 ( 0 hom. )

Consequence

PNP
NM_000270.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 7.74

Variant links:

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]

PNP links:

ENSG00000258908 (HGNC:):

ENSG00000258908 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.903

PP5

Variant 14-20476432-G-C is Pathogenic according to our data. Variant chr14-20476432-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 13991.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PNP	NM_000270.4 link	c.701G>C	p.Arg234Pro	missense_variant	Exon 6 of 6	ENST00000361505.10	NP_000261.2	P00491V9HWH6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PNP	ENST00000361505.10 link	c.701G>C	p.Arg234Pro	missense_variant	Exon 6 of 6	1	NM_000270.4	ENSP00000354532.6		P00491

Frequencies

GnomAD3 genomes

AF:

0.0000657

AC:

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000795

AC:

AN:

251482

Hom.:

AF XY:

0.0000662

AC XY:

AN XY:

135916

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000167

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000177

AC:

259

AN:

1461878

Hom.:

Cov.:

AF XY:

0.000176

AC XY:

128

AN XY:

727240

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.000226

Gnomad4 OTH exome

AF:

0.000116

GnomAD4 genome

AF:

0.0000657

AC:

AN:

152210

Hom.:

Cov.:

AF XY:

0.0000672

AC XY:

AN XY:

74358

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000941

Gnomad4 NFE

AF:

0.000118

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000901

Hom.:

Bravo

AF:

0.0000756

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000107

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Purine-nucleoside phosphorylase deficiency

Pathogenic:4

Apr 21, 2021

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 18, 2018

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Oct 01, 1992

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jan 07, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Severe combined immunodeficiency disease

Pathogenic:1

Sep 18, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Dec 27, 2024

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.58

BayesDel_addAF

Pathogenic

0.23

BayesDel_noAF

Pathogenic

0.35

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.64

Eigen

Pathogenic

0.73

Eigen_PC

Pathogenic

0.70

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.97

M_CAP

Uncertain

0.18

MetaRNN

Pathogenic

0.90

MetaSVM

Uncertain

0.55

MutationAssessor

Benign

1.9

PrimateAI

Uncertain

0.75

PROVEAN

Uncertain

-4.3

REVEL

Pathogenic

0.87

Sift

Uncertain

0.013

Sift4G

Uncertain

0.012

Polyphen

1.0

Vest4

0.89

MVP

0.98

MPC

1.1

ClinPred

0.65

GERP RS

4.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.98

gMVP

0.95

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over