14-20474585-A-G

Variant names:

• chr14-20474585-A-G
• rs1713420
• ENST00000556293.6:n.2408A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000556293.6(PNP):​n.2408A>G variant causes a non coding transcript exon 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 ENST00000556293.6 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.140
• Publications: 18 publications found

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 Gene-Disease associations (from GenCC):

• purine nucleoside phosphorylase deficiency

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet

ENSG00000258908 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 312730.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.311 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000556293.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PNP	NM_000270.4	MANE Select	c.285+10A>G		intron	N/A	NP_000261.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PNP	ENST00000556293.6	TSL:1	n.2408A>G		non_coding_transcript_exon	Exon 2 of 3
	PNP	ENST00000557229.6	TSL:1	n.414A>G		non_coding_transcript_exon	Exon 3 of 4
	PNP	ENST00000361505.10	TSL:1 MANE Select	c.285+10A>G		intron	N/A	ENSP00000354532.6

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

GnomAD2 exomes AF: 0.189 AC: 47543 AN: 251404 AF XY: 0.188

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 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

African (AFR) AF: 0.330 AC: 11001 AN: 33386

American (AMR) AF: 0.153 AC: 6844 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.190 AC: 4972 AN: 26110

East Asian (EAS) AF: 0.132 AC: 5239 AN: 39676

South Asian (SAS) AF: 0.158 AC: 13596 AN: 86142

European-Finnish (FIN) AF: 0.184 AC: 9842 AN: 53410

Middle Eastern (MID) AF: 0.222 AC: 1277 AN: 5756

European-Non Finnish (NFE) AF: 0.205 AC: 227543 AN: 1107768

Other (OTH) AF: 0.204 AC: 12275 AN: 60206

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

African (AFR) AF: 0.316 AC: 13081 AN: 41436

American (AMR) AF: 0.184 AC: 2809 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.188 AC: 651 AN: 3470

East Asian (EAS) AF: 0.117 AC: 605 AN: 5176

South Asian (SAS) AF: 0.146 AC: 703 AN: 4812

European-Finnish (FIN) AF: 0.183 AC: 1938 AN: 10584

Middle Eastern (MID) AF: 0.180 AC: 53 AN: 294

European-Non Finnish (NFE) AF: 0.205 AC: 13933 AN: 67990

Other (OTH) AF: 0.207 AC: 438 AN: 2116

Alfa AF: 0.211 Hom.: 8479

Bravo AF: 0.231

Asia WGS AF: 0.139 AC: 487 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Purine-nucleoside phosphorylase deficiency Benign:4

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

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Jan 13, 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.

not specified Benign:3

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

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.

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	8.7
DANN	Benign	0.47
PhyloP100		-0.14
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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