rs145773529

chr14-20475143-G-Cchr14-20475143-G-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM2 BP4_Strong BP6_Very_Strong BS1

The NM_000270.4(PNP):c.543G>C(p.Met181Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000363 in 1,614,186 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00020 (1 hom.)
• Consequence: PNP NM_000270.4 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.41

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.00886628).
• BP6: Variant 14-20475143-G-C is Benign according to our data. Variant chr14-20475143-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 529210.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-20475143-G-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00195 (297/152306) while in subpopulation AFR AF= 0.00683 (284/41564). AF 95% confidence interval is 0.00618. There are 0 homozygotes in gnomad4. There are 143 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PNP	NM_000270.4	c.543G>C	p.Met181Ile	missense_variant	5/6	ENST00000361505.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PNP	ENST00000361505.10	c.543G>C	p.Met181Ile	missense_variant	5/6	1	NM_000270.4	P1
	ENST00000554678.1	n.187-49C>G		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.00194 AC: 296 AN: 152188 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00683

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

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: 0.0000294

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.000485 AC: 122 AN: 251470 Hom.: 0 AF XY: 0.000427 AC XY: 58 AN XY: 135906

Gnomad AFR exome AF: 0.00683

Gnomad AMR exome AF: 0.000260

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: 0.00000879

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000198 AC: 289 AN: 1461880 Hom.: 1 Cov.: 32 AF XY: 0.000197 AC XY: 143 AN XY: 727244

Gnomad4 AFR exome AF: 0.00786

Gnomad4 AMR exome AF: 0.000268

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.000232

GnomAD4 genome AF: 0.00195 AC: 297 AN: 152306 Hom.: 0 Cov.: 32 AF XY: 0.00192 AC XY: 143 AN XY: 74480

Gnomad4 AFR AF: 0.00683

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.000281 Hom.: 0

Bravo AF: 0.00201

ESP6500AA AF: 0.00499 AC: 22

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000494 AC: 60

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Feb 02, 2023

Variant summary: PNP c.543G>C (p.Met181Ile) results in a conservative amino acid change located in the Nucleoside phosphorylase domain (IPR000845) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00049 in 251470 control chromosomes, predominantly at a frequency of 0.0068 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 19-fold of the estimated maximal expected allele frequency for a pathogenic variant in PNP causing Severe Combined Immunodeficiency phenotype (0.00035), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. To our knowledge, no occurrence of c.543G>C in individuals affected with Severe Combined Immunodeficiency and no experimental evidence demonstrating its impact on protein function have been reported. One submitter has provided a clinical-significance assessment for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as likely benign. -

Purine-nucleoside phosphorylase deficiency Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 20, 2024

- -

PNP-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 27, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.15
Cadd	Benign	21
Dann	Uncertain	0.98
DEOGEN2	Benign	0.27	T;.
Eigen	Benign	-0.055
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.79	T;T
M_CAP	Uncertain	0.096	D
MetaRNN	Benign	0.0089	T;T
MetaSVM	Uncertain	0.064	D
MutationAssessor	Benign	0.46	N;.
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.73	N;N
REVEL	Uncertain	0.39
Sift	Benign	0.16	T;T
Sift4G	Benign	0.20	T;T
Polyphen		0.13	B;.
Vest4		0.25
MutPred		0.52		Loss of disorder (P = 0.026);.;
MVP		0.89
MPC		0.28
ClinPred		0.043	T
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.58
gMVP		0.71

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: rs145773529; hg19: chr14-20943302;