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rs1026474882

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PM2PP5_Very_StrongBP4

The NM_000270.4(PNP):c.286-18G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000329 in 1,612,616 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000036 ( 0 hom. )

Consequence

PNP
NM_000270.4 intron

Scores

2

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 0.00200
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 14-20474755-G-A is Pathogenic according to our data. Variant chr14-20474755-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 505116.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.79).. Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
PNPNM_000270.4 linkuse as main transcriptc.286-18G>A intron_variant ENST00000361505.10

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
PNPENST00000361505.10 linkuse as main transcriptc.286-18G>A intron_variant 1 NM_000270.4 P1
ENST00000554678.1 linkuse as main transcript downstream_gene_variant 5

Frequencies

GnomAD3 genomes
AF:
0.00000658
AC:
1
AN:
152056
Hom.:
0
Cov.:
32
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:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000362
AC:
9
AN:
248566
Hom.:
0
AF XY:
0.0000372
AC XY:
5
AN XY:
134526
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:
0.00
Gnomad NFE exome
AF:
0.0000713
Gnomad OTH exome
AF:
0.000165
GnomAD4 exome
AF:
0.0000356
AC:
52
AN:
1460560
Hom.:
0
Cov.:
32
AF XY:
0.0000317
AC XY:
23
AN XY:
726450
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000432
Gnomad4 OTH exome
AF:
0.0000331
GnomAD4 genome
AF:
0.00000658
AC:
1
AN:
152056
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74272
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:
0.0000147
Gnomad4 OTH
AF:
0.00

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Purine-nucleoside phosphorylase deficiency Pathogenic:4
Pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsDec 13, 2022- -
Likely pathogenic, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineJul 07, 2016The c.286-18G>A variant in PNP has been reported in 2 patients with purine nucle oside phosphorylase deficiency (in the homozygous and compound heterozygous stat e) (la Marca 2014, Markert 1997) and was demonstrated to cause altered splicing leading to a frameshift in patient cells (Markert 1997). This variant was also i dentified in 3/104,620 of chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org). Although this variant has been seen in the gen eral population, its frequency is low enough to be consistent with a recessive c arrier frequency. In summary, although additional studies are needed to clarify its significance, this variant is likely pathogenic. -
Pathogenic, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsOct 31, 2018- -
Pathogenic, criteria provided, single submitterclinical testingInvitaeFeb 05, 2022This sequence change falls in intron 3 of the PNP gene. It does not directly change the encoded amino acid sequence of the PNP protein. This variant is present in population databases (no rsID available, gnomAD 0.006%). This variant has been observed in individual(s) with purine nucleoside phosphorylase deficiency (PMID: 9067751, 24767876; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 505116). Studies have shown that this variant is associated with altered splicing, but the impact on the resulting protein product is unknown (PMID: 9067751). For these reasons, this variant has been classified as Pathogenic. -
Severe combined immunodeficiency disease Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpNov 16, 2023Variant summary: PNP c.286-18G>A alters a non-conserved nucleotide located at a position not widely known to affect splicing. However, several computational tools predict a significant impact on normal splicing: Three predict the variant weakens a canonical 3' splicing acceptor site, and four predict the variant creates a cryptic 3' acceptor site 16 bp upstream of the canonical site. At least one publication reports experimental evidence that this variant affects mRNA splicing, resulting in a 16 bp insertion expected to result in a frameshift (Markert_1997). The variant allele was found at a frequency of 3.6e-05 in 248566 control chromosomes (gnomAD). c.286-18G>A has been reported in the literature in multiple individuals affected with Combined Immunodeficiency (Markert_1997, Somech_2013, la Marca_2014, Vignesh_2021), and one patient was compound heterozygous with another pathogenic variant. A homozygous case showed no detectible PNP activity, while their heterozygous parents showed roughly half of normal activity (Somech_2013). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 9067751, 24767876, 23371835, 33628209). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.79
Cadd
Benign
7.1
Dann
Benign
0.92
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
1.0
Details are displayed if max score is > 0.2
DS_AG_spliceai
1.0
Position offset: 2
DS_AL_spliceai
1.0
Position offset: 18

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.

Other links and lift over

dbSNP: rs1026474882; hg19: chr14-20942914; API