14-20469434-G-T

Variant names:

• chr14-20469434-G-T
• rs115464597
• NM_000270.4:c.-91G>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_000270.4(PNP):​c.-91G>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00102 in 1,513,898 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0053 (10 hom., cov: 32)
  • Exomes 𝑓: 0.00054 (8 hom.)
• Consequence: PNP NM_000270.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.675
• Publications: 1 publications found

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

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 14-20469434-G-T is Benign according to our data. Variant chr14-20469434-G-T is described in ClinVar as Benign. ClinVar VariationId is 312725.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00526 (801/152320) while in subpopulation AFR AF = 0.0184 (763/41574). AF 95% confidence interval is 0.0173. There are 10 homozygotes in GnomAd4. There are 396 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 10 AR gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PNP	NM_000270.4	MANE Select	c.-91G>T		5_prime_UTR	Exon 1 of 6	NP_000261.2	P00491

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PNP	ENST00000361505.10	TSL:1 MANE Select	c.-91G>T		5_prime_UTR	Exon 1 of 6	ENSP00000354532.6	P00491
	PNP	ENST00000556293.6	TSL:1	n.29G>T		non_coding_transcript_exon	Exon 1 of 3
	PNP	ENST00000557229.6	TSL:1	n.29G>T		non_coding_transcript_exon	Exon 1 of 4

Frequencies

GnomAD3 genomes AF: 0.00525 AC: 799 AN: 152202 Hom.: 10 Cov.: 32

Gnomad AFR AF: 0.0184

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00144

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00430

GnomAD4 exome AF: 0.000541 AC: 736 AN: 1361578 Hom.: 8 Cov.: 25 AF XY: 0.000466 AC XY: 314 AN XY: 673692

African (AFR) AF: 0.0178 AC: 547 AN: 30762

American (AMR) AF: 0.00104 AC: 37 AN: 35668

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24934

East Asian (EAS) AF: 0.00101 AC: 36 AN: 35590

South Asian (SAS) AF: 0.000153 AC: 12 AN: 78454

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49276

Middle Eastern (MID) AF: 0.000249 AC: 1 AN: 4022

European-Non Finnish (NFE) AF: 0.0000564 AC: 59 AN: 1046238

Other (OTH) AF: 0.000777 AC: 44 AN: 56634

GnomAD4 genome AF: 0.00526 AC: 801 AN: 152320 Hom.: 10 Cov.: 32 AF XY: 0.00532 AC XY: 396 AN XY: 74486

African (AFR) AF: 0.0184 AC: 763 AN: 41574

American (AMR) AF: 0.00144 AC: 22 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68020

Other (OTH) AF: 0.00425 AC: 9 AN: 2116

Alfa AF: 0.00145 Hom.: 0

Bravo AF: 0.00598

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Purine-nucleoside phosphorylase deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	6.1
DANN	Benign	0.74
PhyloP100		0.68
PromoterAI		-0.053	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=300/0	polymorphism

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

Other links and lift over

dbSNP: rs115464597; hg19: chr14-20937593;