rs1713420

Positions:

• chr14-20474585-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000270.4(PNP):​c.285+10A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.203 in 1,609,246 control chromosomes in the GnomAD database, including 34,698 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (4220 hom., cov: 32)
  • Exomes 𝑓: 0.20 (30478 hom.)
• Consequence: PNP NM_000270.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.140

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 14-20474585-A-G is Benign according to our data. Variant chr14-20474585-A-G is described in ClinVar as [Benign]. Clinvar id is 312730.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-20474585-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.311 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PNP	NM_000270.4	c.285+10A>G		intron_variant		ENST00000361505.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PNP	ENST00000361505.10	c.285+10A>G		intron_variant		1	NM_000270.4	P1

Frequencies

GnomAD3 genomes AF: 0.226 AC: 34319 AN: 151960 Hom.: 4209 Cov.: 32

Gnomad AFR AF: 0.315

Gnomad AMI AF: 0.171

Gnomad AMR AF: 0.184

Gnomad ASJ AF: 0.188

Gnomad EAS AF: 0.117

Gnomad SAS AF: 0.146

Gnomad FIN AF: 0.183

Gnomad MID AF: 0.187

Gnomad NFE AF: 0.205

Gnomad OTH AF: 0.208

GnomAD3 exomes AF: 0.189 AC: 47543 AN: 251404 Hom.: 4930 AF XY: 0.188 AC XY: 25539 AN XY: 135868

Gnomad AFR exome AF: 0.318

Gnomad AMR exome AF: 0.145

Gnomad ASJ exome AF: 0.186

Gnomad EAS exome AF: 0.107

Gnomad SAS exome AF: 0.158

Gnomad FIN exome AF: 0.185

Gnomad NFE exome AF: 0.206

Gnomad OTH exome AF: 0.199

GnomAD4 exome AF: 0.201 AC: 292589 AN: 1457168 Hom.: 30478 Cov.: 29 AF XY: 0.199 AC XY: 144582 AN XY: 725252

Gnomad4 AFR exome AF: 0.330

Gnomad4 AMR exome AF: 0.153

Gnomad4 ASJ exome AF: 0.190

Gnomad4 EAS exome AF: 0.132

Gnomad4 SAS exome AF: 0.158

Gnomad4 FIN exome AF: 0.184

Gnomad4 NFE exome AF: 0.205

Gnomad4 OTH exome AF: 0.204

GnomAD4 genome AF: 0.226 AC: 34367 AN: 152078 Hom.: 4220 Cov.: 32 AF XY: 0.222 AC XY: 16484 AN XY: 74348

Gnomad4 AFR AF: 0.316

Gnomad4 AMR AF: 0.184

Gnomad4 ASJ AF: 0.188

Gnomad4 EAS AF: 0.117

Gnomad4 SAS AF: 0.146

Gnomad4 FIN AF: 0.183

Gnomad4 NFE AF: 0.205

Gnomad4 OTH AF: 0.207

Alfa AF: 0.212 Hom.: 2927

Bravo AF: 0.231

Asia WGS AF: 0.139 AC: 487 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Purine-nucleoside phosphorylase deficiency Benign:4

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Oct 25, 2021	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Jan 24, 2024	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. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	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 -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	8.7
DANN	Benign	0.47

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: rs1713420; hg19: chr14-20942744; COSMIC: COSV64092396; COSMIC: COSV64092396;