14-20469429-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_000270.4(PNP):c.-96G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00515 in 1,499,862 control chromosomes in the GnomAD database, including 70 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0039 (8 hom., cov: 32)
  • Exomes 𝑓: 0.0053 (62 hom.)
• Consequence: PNP NM_000270.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.109

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 14-20469429-G-A is Benign according to our data. Variant chr14-20469429-G-A is described in ClinVar as [Benign]. Clinvar id is 312724.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00393 (599/152312) while in subpopulation SAS AF= 0.0197 (95/4832). AF 95% confidence interval is 0.0165. There are 8 homozygotes in gnomad4. There are 312 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PNP	NM_000270.4	c.-96G>A		5_prime_UTR_variant	1/6	ENST00000361505.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PNP	ENST00000361505.10	c.-96G>A		5_prime_UTR_variant	1/6	1	NM_000270.4	P1

Frequencies

GnomAD3 genomes AF: 0.00394 AC: 599 AN: 152194 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.00128

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00216

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00173

Gnomad SAS AF: 0.0199

Gnomad FIN AF: 0.00179

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00550

Gnomad OTH AF: 0.00669

GnomAD4 exome AF: 0.00529 AC: 7124 AN: 1347550 Hom.: 62 Cov.: 24 AF XY: 0.00582 AC XY: 3885 AN XY: 667418

Gnomad4 AFR exome AF: 0.00131

Gnomad4 AMR exome AF: 0.00222

Gnomad4 ASJ exome AF: 0.000121

Gnomad4 EAS exome AF: 0.000591

Gnomad4 SAS exome AF: 0.0195

Gnomad4 FIN exome AF: 0.00191

Gnomad4 NFE exome AF: 0.00485

Gnomad4 OTH exome AF: 0.00517

GnomAD4 genome AF: 0.00393 AC: 599 AN: 152312 Hom.: 8 Cov.: 32 AF XY: 0.00419 AC XY: 312 AN XY: 74502

Gnomad4 AFR AF: 0.00127

Gnomad4 AMR AF: 0.00216

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00193

Gnomad4 SAS AF: 0.0197

Gnomad4 FIN AF: 0.00179

Gnomad4 NFE AF: 0.00550

Gnomad4 OTH AF: 0.00662

Alfa AF: 0.00124 Hom.: 0

Bravo AF: 0.00332

Asia WGS AF: 0.00866 AC: 30 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Purine-nucleoside phosphorylase deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
Cadd	Benign	1.4
Dann	Benign	0.86
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.2

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

LitVar

Other links and lift over

dbSNP: rs17881206; hg19: chr14-20937588;