14-20469534-G-C

Position:

chr14-20469534-G-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_000270.4(PNP):c.10G>C(p.Gly4Arg) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000811 in 1,554,188 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 18/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000085 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000081 ( 0 hom. )

Consequence

PNP
NM_000270.4 missense, splice_region

Scores

Splicing: ADA: 0.00005941

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.06

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.04977569).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PNP	NM_000270.4 linkuse as main transcript	c.10G>C	p.Gly4Arg	missense_variant, splice_region_variant	1/6	ENST00000361505.10	NP_000261.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PNP	ENST00000361505.10 linkuse as main transcript	c.10G>C	p.Gly4Arg	missense_variant, splice_region_variant	1/6	1	NM_000270.4	ENSP00000354532	P1

Frequencies

GnomAD3 genomes

AF:

0.0000855

AC:

AN:

152076

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000191

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000880

AC:

AN:

159098

Hom.:

AF XY:

0.000119

AC XY:

AN XY:

83974

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.0000638

Gnomad NFE exome

AF:

0.000195

Gnomad OTH exome

AF:

0.000221

GnomAD4 exome

AF:

0.0000806

AC:

113

AN:

1402112

Hom.:

Cov.:

AF XY:

0.0000997

AC XY:

AN XY:

691882

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:

0.0000202

Gnomad4 NFE exome

AF:

0.0000990

Gnomad4 OTH exome

AF:

0.0000687

GnomAD4 genome

AF:

0.0000855

AC:

AN:

152076

Hom.:

Cov.:

AF XY:

0.0000808

AC XY:

AN XY:

74302

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000191

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000203

Hom.:

Bravo

AF:

0.0000567

ExAC

AF:

0.0000274

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Purine-nucleoside phosphorylase deficiency

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 27, 2023

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 4 of the PNP protein (p.Gly4Arg). This variant is present in population databases (rs764019813, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with PNP-related conditions. ClinVar contains an entry for this variant (Variation ID: 459611). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The arginine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.27

CADD

Benign

3.9

DANN

Benign

0.90

DEOGEN2

Benign

0.0029

T;T

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.57

T;T

M_CAP

Benign

0.036

MetaRNN

Benign

0.050

T;T

MetaSVM

Benign

-0.78

MutationAssessor

Benign

-0.075

.;N

MutationTaster

Benign

1.0

PrimateAI

Benign

0.23

PROVEAN

Benign

-0.10

N;N

REVEL

Benign

0.26

Sift

Benign

0.39

T;T

Sift4G

Benign

0.50

T;T

Polyphen

0.0

B;B

Vest4

0.088

MutPred

0.18

Gain of helix (P = 0.0164);Gain of helix (P = 0.0164);

MVP

0.63

MPC

0.30

ClinPred

0.021

GERP RS

-2.2

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

3.0

Varity_R

0.066

gMVP

0.68

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000059

dbscSNV1_RF

Benign

0.028

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