rs1026474882

chr14-20474755-G-Achr14-20474755-G-Cchr14-20474755-G-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong

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

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]

PNP links:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PNP	NM_000270.4 linkuse as main transcript	c.286-18G>A		intron_variant		ENST00000361505.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PNP	ENST00000361505.10 linkuse as main transcript	c.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:

AN:

152056

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000362

AC:

AN:

248566

Hom.:

AF XY:

0.0000372

AC XY:

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:

AN:

1460560

Hom.:

Cov.:

AF XY:

0.0000317

AC XY:

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:

AN:

152056

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

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 submitter	clinical testing	Baylor Genetics	Dec 13, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Feb 05, 2022	This 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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 07, 2016	The 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 submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -

Severe combined immunodeficiency disease

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Nov 16, 2023

Variant 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.

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