Genetic Variant PNP:p.Arg234Leu (chr14-20476432-G-T) – ACMG Classification: Likely_pathogenic (8 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1PM2PM5PP3_Moderate

The NM_000270.4(PNP):c.701G>T(p.Arg234Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,878 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. R234P) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

PNP
NM_000270.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.74

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

PNP links:

ENSG00000258908 (HGNC:):

ENSG00000258908 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 8 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;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr14-20476432-G-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 13991.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.888

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PNP	NM_000270.4	MANE Select	c.701G>T	p.Arg234Leu	missense	Exon 6 of 6	NP_000261.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PNP	ENST00000361505.10	TSL:1 MANE Select	c.701G>T	p.Arg234Leu	missense	Exon 6 of 6	ENSP00000354532.6
PNP	ENST00000556293.6	TSL:1	n.3124G>T		non_coding_transcript_exon	Exon 3 of 3
PNP	ENST00000557229.6	TSL:1	n.1130G>T		non_coding_transcript_exon	Exon 4 of 4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461878

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727240

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1112000

Other (OTH)

AF:

0.00

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.43

BayesDel_addAF

Pathogenic

0.46

BayesDel_noAF

Pathogenic

0.42

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.75

Eigen

Pathogenic

0.87

Eigen_PC

Pathogenic

0.79

FATHMM_MKL

Uncertain

0.96

LIST_S2

Pathogenic

0.99

M_CAP

Uncertain

0.15

MetaRNN

Pathogenic

0.89

MetaSVM

Pathogenic

0.86

MutationAssessor

Pathogenic

3.9

PhyloP100

7.7

PrimateAI

Uncertain

0.74

PROVEAN

Pathogenic

-4.4

REVEL

Pathogenic

0.87

Sift

Uncertain

0.015

Sift4G

Uncertain

0.015

Polyphen

1.0

Vest4

0.73

MutPred

0.67

Loss of catalytic residue at R234 (P = 0.0236)

MVP

0.99

MPC

0.99

ClinPred

1.0

GERP RS

4.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.94

gMVP

0.88

Mutation Taster

=14/86

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over