Genetic Variant PNP:p.Gly51Arg (chr14-20472447-G-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate

The NM_000270.4(PNP):c.151G>C(p.Gly51Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,461,348 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G51S) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

PNP
NM_000270.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.61

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

purine nucleoside phosphorylase deficiency
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Orphanet

PNP links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 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

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.13265917).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000270.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PNP	NM_000270.4	MANE Select	c.151G>C	p.Gly51Arg	missense	Exon 2 of 6	NP_000261.2	P00491

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PNP	ENST00000361505.10	TSL:1 MANE Select	c.151G>C	p.Gly51Arg	missense	Exon 2 of 6	ENSP00000354532.6	P00491
PNP	ENST00000556293.6	TSL:1	n.270G>C		non_coding_transcript_exon	Exon 2 of 3
PNP	ENST00000557229.6	TSL:1	n.270G>C		non_coding_transcript_exon	Exon 2 of 4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000616

AC:

AN:

1461348

Hom.:

Cov.:

AF XY:

0.00000825

AC XY:

AN XY:

727018

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33464

American (AMR)

AF:

0.00

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86244

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00000810

AC:

AN:

1111524

Other (OTH)

AF:

0.00

AC:

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Uncertain

0.096

BayesDel_noAF

Benign

-0.10

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0094

Eigen

Benign

-0.60

Eigen_PC

Benign

-0.42

FATHMM_MKL

Benign

0.31

LIST_S2

Uncertain

0.96

M_CAP

Uncertain

0.15

MetaRNN

Benign

0.13

MetaSVM

Benign

-0.31

MutationAssessor

Benign

0.34

PhyloP100

1.6

PrimateAI

Benign

0.34

PROVEAN

Benign

1.3

REVEL

Benign

0.28

Sift

Benign

0.094

Sift4G

Benign

0.26

Polyphen

0.0

Vest4

0.12

MutPred

0.40

Gain of solvent accessibility (P = 0.0014)

MVP

0.85

MPC

0.30

ClinPred

0.24

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.11

gMVP

0.61

Mutation Taster

=99/1

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over