Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS1

The NM_000270.4(PNP):c.653-4T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000161 in 1,610,558 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00093 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000081 ( 0 hom. )

Consequence

PNP
NM_000270.4 splice_region, intron

Scores

Splicing: ADA: 0.00005511

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.393

Publications

0 publications found

Variant links:

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

PNP links:

ENSG00000258908 (HGNC:):

ENSG00000258908 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.69).

BP6

Variant 14-20476380-T-C is Benign according to our data. Variant chr14-20476380-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 391026.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000926 (141/152338) while in subpopulation AFR AF = 0.00289 (120/41578). AF 95% confidence interval is 0.00247. There are 0 homozygotes in GnomAd4. There are 64 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PNP	NM_000270.4	MANE Select	c.653-4T>C		splice_region intron	N/A	NP_000261.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
PNP	ENST00000361505.10	TSL:1 MANE Select	c.653-4T>C	splice_region intron	N/A	ENSP00000354532.6
PNP	ENST00000556293.6	TSL:1	n.3076-4T>C	splice_region intron	N/A
PNP	ENST00000557229.6	TSL:1	n.1082-4T>C	splice_region intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.000926

AC:

141

AN:

152220

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00289

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00124

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:

0.00

GnomAD2 exomes

AF:

0.000219

AC:

AN:

251438

AF XY:

0.000147

show subpopulations

Gnomad AFR exome

AF:

0.00215

Gnomad AMR exome

AF:

0.000318

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000616

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.0000809

AC:

118

AN:

1458220

Hom.:

Cov.:

AF XY:

0.0000841

AC XY:

AN XY:

725696

show subpopulations

African (AFR)

AF:

0.00180

AC:

AN:

33400

American (AMR)

AF:

0.000492

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26112

East Asian (EAS)

AF:

0.00

AC:

AN:

39686

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86128

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.000358

AC:

AN:

5586

European-Non Finnish (NFE)

AF:

0.0000162

AC:

AN:

1108914

Other (OTH)

AF:

0.000249

AC:

AN:

60252

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000926

AC:

141

AN:

152338

Hom.:

Cov.:

AF XY:

0.000859

AC XY:

AN XY:

74480

show subpopulations

African (AFR)

AF:

0.00289

AC:

120

AN:

41578

American (AMR)

AF:

0.00124

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68040

Other (OTH)

AF:

0.00

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000343

Hom.:

Bravo

AF:

0.000842

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000178

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (2)

PNP-related disorder (1)

Purine-nucleoside phosphorylase deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.69

CADD

Benign

5.6

(source)

DANN

Benign

0.75

PhyloP100

-0.39

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000055

dbscSNV1_RF

Benign

0.0

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

rs199866228

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over