14-20472467-C-T

Variant names:

• chr14-20472467-C-T
• rs1130650
• NM_000270.4:c.171C>T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000270.4(PNP):​c.171C>T​(p.Pro57Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.185 in 1,609,224 control chromosomes in the GnomAD database, including 28,595 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (3216 hom., cov: 32)
  • Exomes 𝑓: 0.18 (25379 hom.)
• Consequence: PNP NM_000270.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.723

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP6: Variant 14-20472467-C-T is Benign according to our data. Variant chr14-20472467-C-T is described in ClinVar as [Benign]. Clinvar id is 138730.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-20472467-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.723 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.247 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PNP	NM_000270.4	c.171C>T	p.Pro57Pro	synonymous_variant	Exon 2 of 6	ENST00000361505.10	NP_000261.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PNP	ENST00000361505.10	c.171C>T	p.Pro57Pro	synonymous_variant	Exon 2 of 6	1	NM_000270.4	ENSP00000354532.6

Frequencies

GnomAD3 genomes AF: 0.203 AC: 30917 AN: 152070 Hom.: 3207 Cov.: 32

Gnomad AFR AF: 0.251

Gnomad AMI AF: 0.212

Gnomad AMR AF: 0.221

Gnomad ASJ AF: 0.201

Gnomad EAS AF: 0.200

Gnomad SAS AF: 0.142

Gnomad FIN AF: 0.159

Gnomad MID AF: 0.180

Gnomad NFE AF: 0.182

Gnomad OTH AF: 0.189

GnomAD3 exomes AF: 0.191 AC: 48051 AN: 251190 Hom.: 4732 AF XY: 0.187 AC XY: 25416 AN XY: 135770

Gnomad AFR exome AF: 0.250

Gnomad AMR exome AF: 0.235

Gnomad ASJ exome AF: 0.199

Gnomad EAS exome AF: 0.194

Gnomad SAS exome AF: 0.154

Gnomad FIN exome AF: 0.165

Gnomad NFE exome AF: 0.183

Gnomad OTH exome AF: 0.194

GnomAD4 exome AF: 0.183 AC: 267158 AN: 1457036 Hom.: 25379 Cov.: 32 AF XY: 0.182 AC XY: 132006 AN XY: 725124

Gnomad4 AFR exome AF: 0.257

Gnomad4 AMR exome AF: 0.234

Gnomad4 ASJ exome AF: 0.205

Gnomad4 EAS exome AF: 0.210

Gnomad4 SAS exome AF: 0.152

Gnomad4 FIN exome AF: 0.164

Gnomad4 NFE exome AF: 0.181

Gnomad4 OTH exome AF: 0.189

GnomAD4 genome AF: 0.203 AC: 30962 AN: 152188 Hom.: 3216 Cov.: 32 AF XY: 0.201 AC XY: 14956 AN XY: 74400

Gnomad4 AFR AF: 0.251

Gnomad4 AMR AF: 0.223

Gnomad4 ASJ AF: 0.201

Gnomad4 EAS AF: 0.200

Gnomad4 SAS AF: 0.143

Gnomad4 FIN AF: 0.159

Gnomad4 NFE AF: 0.182

Gnomad4 OTH AF: 0.189

Alfa AF: 0.187 Hom.: 5311

Bravo AF: 0.211

Asia WGS AF: 0.171 AC: 596 AN: 3478

EpiCase AF: 0.180

EpiControl AF: 0.187

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Jan 24, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 36% of patients studied by a panel of primary immunodeficiencies. Number of patients: 34. Only high quality variants are reported. -

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 07, 2013

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Purine-nucleoside phosphorylase deficiency Benign:4

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 25, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	4.0
DANN	Benign	0.72
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Other links and lift over

dbSNP: rs1130650; hg19: chr14-20940626; COSMIC: COSV64091843; COSMIC: COSV64091843;