rs1049564

Variant names:

• chr14-20472447-G-A
• rs1049564
• NM_000270.4:c.151G>A

Your query was ambiguous. Multiple possible variants found:

• chr14-20472447-G-A
• chr14-20472447-G-C

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

The NM_000270.4(PNP):​c.151G>A​(p.Gly51Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.185 in 1,610,040 control chromosomes in the GnomAD database, including 28,649 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. G51G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.20 (3257 hom., cov: 32)
  • Exomes 𝑓: 0.18 (25392 hom.)
• Consequence: PNP NM_000270.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 1.61
• Publications: 69 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

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• PM1: In a chain Purine nucleoside phosphorylase (size 288) in uniprot entity PNPH_HUMAN there are 12 pathogenic changes around while only 3 benign (80%) in NM_000270.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.0010126531).
• BP6: Variant 14-20472447-G-A is Benign according to our data. Variant chr14-20472447-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 13992.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.251 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PNP	NM_000270.4	c.151G>A	p.Gly51Ser	missense_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.151G>A	p.Gly51Ser	missense_variant	Exon 2 of 6	1	NM_000270.4	ENSP00000354532.6

Frequencies

GnomAD3 genomes AF: 0.204 AC: 31071 AN: 152040 Hom.: 3248 Cov.: 32

Gnomad AFR AF: 0.255

Gnomad AMI AF: 0.212

Gnomad AMR AF: 0.222

Gnomad ASJ AF: 0.201

Gnomad EAS AF: 0.199

Gnomad SAS AF: 0.141

Gnomad FIN AF: 0.159

Gnomad MID AF: 0.180

Gnomad NFE AF: 0.182

Gnomad OTH AF: 0.192

GnomAD2 exomes AF: 0.191 AC: 48099 AN: 251310 AF XY: 0.187

Gnomad AFR exome AF: 0.254

Gnomad AMR exome AF: 0.235

Gnomad ASJ exome AF: 0.200

Gnomad EAS exome AF: 0.193

Gnomad FIN exome AF: 0.165

Gnomad NFE exome AF: 0.183

Gnomad OTH exome AF: 0.194

GnomAD4 exome AF: 0.183 AC: 267373 AN: 1457882 Hom.: 25392 Cov.: 32 AF XY: 0.182 AC XY: 132081 AN XY: 725496

African (AFR) AF: 0.262 AC: 8751 AN: 33358

American (AMR) AF: 0.234 AC: 10462 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.205 AC: 5360 AN: 26118

East Asian (EAS) AF: 0.209 AC: 8288 AN: 39682

South Asian (SAS) AF: 0.152 AC: 13105 AN: 86188

European-Finnish (FIN) AF: 0.164 AC: 8762 AN: 53412

Middle Eastern (MID) AF: 0.207 AC: 1190 AN: 5752

European-Non Finnish (NFE) AF: 0.181 AC: 200076 AN: 1108396

Other (OTH) AF: 0.189 AC: 11379 AN: 60260

GnomAD4 genome AF: 0.205 AC: 31118 AN: 152158 Hom.: 3257 Cov.: 32 AF XY: 0.202 AC XY: 15040 AN XY: 74376

African (AFR) AF: 0.255 AC: 10595 AN: 41506

American (AMR) AF: 0.223 AC: 3405 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.201 AC: 697 AN: 3464

East Asian (EAS) AF: 0.199 AC: 1029 AN: 5170

South Asian (SAS) AF: 0.142 AC: 683 AN: 4816

European-Finnish (FIN) AF: 0.159 AC: 1690 AN: 10602

Middle Eastern (MID) AF: 0.177 AC: 52 AN: 294

European-Non Finnish (NFE) AF: 0.182 AC: 12371 AN: 68006

Other (OTH) AF: 0.191 AC: 403 AN: 2106

Alfa AF: 0.190 Hom.: 10528

Bravo AF: 0.213

TwinsUK AF: 0.189 AC: 702

ALSPAC AF: 0.193 AC: 745

ESP6500AA AF: 0.246 AC: 1083

ESP6500EA AF: 0.177 AC: 1522

ExAC AF: 0.192 AC: 23292

Asia WGS AF: 0.172 AC: 597 AN: 3478

EpiCase AF: 0.180

EpiControl AF: 0.186

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Dec 03, 2021

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

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.

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

Purine-nucleoside phosphorylase deficiency Benign:5

Mar 06, 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.

Dec 14, 2021

Fulgent Genetics, Fulgent Genetics

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

Oct 25, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PNP POLYMORPHISM Benign:1

Oct 01, 1992

OMIM

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: literature only

not provided Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	15
DANN	Benign	0.70
DEOGEN2	Benign	0.0050	T;T;.
Eigen	Benign	-0.95
Eigen_PC	Benign	-0.68
FATHMM_MKL	Benign	0.084	N
LIST_S2	Benign	0.66	T;T;T
MetaRNN	Benign	0.0010	T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.0	.;N;.
PhyloP100		1.6
PrimateAI	Benign	0.31	T
PROVEAN	Benign	2.4	N;N;N
REVEL	Uncertain	0.30
Sift	Benign	1.0	T;T;T
Sift4G	Benign	0.84	T;T;T
Vest4		0.0
ClinPred		0.0097	T
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.084
gMVP		0.45
Mutation Taster		=97/3	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: rs1049564; hg19: chr14-20940606; COSMIC: COSV64091839; COSMIC: COSV64091839;