NM_000270.4:c.12-18A>T

Variant names:

• chr14-20472290-A-T
• rs117497269
• NM_000270.4:c.12-18A>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000270.4(PNP):​c.12-18A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00506 in 1,610,304 control chromosomes in the GnomAD database, including 72 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0037 (8 hom., cov: 32)
  • Exomes 𝑓: 0.0052 (64 hom.)
• Consequence: PNP NM_000270.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.32
• Publications: 2 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 14-20472290-A-T is Benign according to our data. Variant chr14-20472290-A-T is described in ClinVar as Benign. ClinVar VariationId is 138728.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00371 (565/152262) while in subpopulation SAS AF = 0.0191 (92/4826). AF 95% confidence interval is 0.0159. There are 8 homozygotes in GnomAd4. There are 292 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 8 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.12-18A>T		intron	N/A	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.12-18A>T		intron	N/A	ENSP00000354532.6	P00491
	PNP	ENST00000556293.6	TSL:1	n.131-18A>T		intron	N/A
	PNP	ENST00000557229.6	TSL:1	n.131-18A>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00371 AC: 565 AN: 152144 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.000845

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00210

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00173

Gnomad SAS AF: 0.0193

Gnomad FIN AF: 0.00170

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00535

Gnomad OTH AF: 0.00621

GnomAD2 exomes AF: 0.00555 AC: 1395 AN: 251462 AF XY: 0.00653

Gnomad AFR exome AF: 0.000677

Gnomad AMR exome AF: 0.00214

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00152

Gnomad FIN exome AF: 0.00176

Gnomad NFE exome AF: 0.00543

Gnomad OTH exome AF: 0.00407

GnomAD4 exome AF: 0.00520 AC: 7578 AN: 1458042 Hom.: 64 Cov.: 29 AF XY: 0.00573 AC XY: 4155 AN XY: 725628

African (AFR) AF: 0.00105 AC: 35 AN: 33374

American (AMR) AF: 0.00224 AC: 100 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.000115 AC: 3 AN: 26104

East Asian (EAS) AF: 0.000680 AC: 27 AN: 39678

South Asian (SAS) AF: 0.0195 AC: 1676 AN: 86160

European-Finnish (FIN) AF: 0.00185 AC: 99 AN: 53410

Middle Eastern (MID) AF: 0.0108 AC: 60 AN: 5564

European-Non Finnish (NFE) AF: 0.00476 AC: 5276 AN: 1108796

Other (OTH) AF: 0.00501 AC: 302 AN: 60234

GnomAD4 genome AF: 0.00371 AC: 565 AN: 152262 Hom.: 8 Cov.: 32 AF XY: 0.00392 AC XY: 292 AN XY: 74468

African (AFR) AF: 0.000843 AC: 35 AN: 41542

American (AMR) AF: 0.00209 AC: 32 AN: 15294

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

East Asian (EAS) AF: 0.00193 AC: 10 AN: 5186

South Asian (SAS) AF: 0.0191 AC: 92 AN: 4826

European-Finnish (FIN) AF: 0.00170 AC: 18 AN: 10610

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00535 AC: 364 AN: 68016

Other (OTH) AF: 0.00615 AC: 13 AN: 2114

Alfa AF: 0.00427 Hom.: 1

Bravo AF: 0.00314

Asia WGS AF: 0.0120 AC: 40 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	not specified (1)
-	-	1	Purine-nucleoside phosphorylase deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.047
DANN	Benign	0.69
PhyloP100		-1.3
Mutation Taster		=100/0	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: rs117497269; hg19: chr14-20940449;