14-20472356-C-T

Variant names:

• chr14-20472356-C-T
• rs1049562
• NM_000270.4:c.60C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000270.4(PNP):​c.60C>T​(p.His20His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.171 in 1,612,038 control chromosomes in the GnomAD database, including 24,374 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (2494 hom., cov: 32)
  • Exomes 𝑓: 0.17 (21880 hom.)
• Consequence: PNP NM_000270.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.933
• Publications: 35 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: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.57).
• BP6: Variant 14-20472356-C-T is Benign according to our data. Variant chr14-20472356-C-T is described in ClinVar as Benign. ClinVar VariationId is 138729.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.933 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.213 is higher than 0.05.

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.60C>T	p.His20His	synonymous	Exon 2 of 6	NP_000261.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PNP	ENST00000361505.10	TSL:1 MANE Select	c.60C>T	p.His20His	synonymous	Exon 2 of 6	ENSP00000354532.6
	PNP	ENST00000556293.6	TSL:1	n.179C>T		non_coding_transcript_exon	Exon 2 of 3
	PNP	ENST00000557229.6	TSL:1	n.179C>T		non_coding_transcript_exon	Exon 2 of 4

Frequencies

GnomAD3 genomes AF: 0.178 AC: 27050 AN: 152042 Hom.: 2493 Cov.: 32

Gnomad AFR AF: 0.217

Gnomad AMI AF: 0.166

Gnomad AMR AF: 0.150

Gnomad ASJ AF: 0.182

Gnomad EAS AF: 0.126

Gnomad SAS AF: 0.154

Gnomad FIN AF: 0.142

Gnomad MID AF: 0.127

Gnomad NFE AF: 0.172

Gnomad OTH AF: 0.161

GnomAD2 exomes AF: 0.163 AC: 40909 AN: 251476 AF XY: 0.164

Gnomad AFR exome AF: 0.219

Gnomad AMR exome AF: 0.124

Gnomad ASJ exome AF: 0.183

Gnomad EAS exome AF: 0.121

Gnomad FIN exome AF: 0.146

Gnomad NFE exome AF: 0.174

Gnomad OTH exome AF: 0.166

GnomAD4 exome AF: 0.170 AC: 248809 AN: 1459878 Hom.: 21880 Cov.: 31 AF XY: 0.170 AC XY: 123708 AN XY: 726354

African (AFR) AF: 0.224 AC: 7484 AN: 33430

American (AMR) AF: 0.129 AC: 5789 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.187 AC: 4885 AN: 26122

East Asian (EAS) AF: 0.137 AC: 5443 AN: 39698

South Asian (SAS) AF: 0.160 AC: 13767 AN: 86228

European-Finnish (FIN) AF: 0.146 AC: 7803 AN: 53416

Middle Eastern (MID) AF: 0.198 AC: 1139 AN: 5758

European-Non Finnish (NFE) AF: 0.173 AC: 192052 AN: 1110164

Other (OTH) AF: 0.173 AC: 10447 AN: 60338

GnomAD4 genome AF: 0.178 AC: 27069 AN: 152160 Hom.: 2494 Cov.: 32 AF XY: 0.175 AC XY: 13001 AN XY: 74378

African (AFR) AF: 0.217 AC: 9000 AN: 41512

American (AMR) AF: 0.150 AC: 2294 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.182 AC: 632 AN: 3468

East Asian (EAS) AF: 0.126 AC: 650 AN: 5174

South Asian (SAS) AF: 0.155 AC: 745 AN: 4820

European-Finnish (FIN) AF: 0.142 AC: 1504 AN: 10576

Middle Eastern (MID) AF: 0.122 AC: 36 AN: 294

European-Non Finnish (NFE) AF: 0.172 AC: 11718 AN: 67998

Other (OTH) AF: 0.161 AC: 339 AN: 2108

Alfa AF: 0.170 Hom.: 4993

Bravo AF: 0.180

Asia WGS AF: 0.129 AC: 448 AN: 3478

EpiCase AF: 0.172

EpiControl AF: 0.178

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	4	Purine-nucleoside phosphorylase deficiency (4)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
CADD	Benign	1.4
DANN	Benign	0.66
PhyloP100		-0.93
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

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: rs1049562; hg19: chr14-20940515; COSMIC: COSV64091826; COSMIC: COSV64091826;