chr14-20469543-G-C

Variant names:

• chr14-20469543-G-C
• rs1274267125
• NM_000270.4:c.11+8G>C

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_000270.4(PNP):​c.11+8G>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 0.000000713 in 1,402,524 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: not found (cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: PNP NM_000270.4 splice_region, intron
• Scores: Splicing: ADA: 0.00003897
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.452
• Publications: 0 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: ClinGen, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 14-20469543-G-C is Benign according to our data. Variant chr14-20469543-G-C is described in ClinVar as Likely_benign. ClinVar VariationId is 3643778.Status of the report is criteria_provided_single_submitter, 1 stars.

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.11+8G>C		splice_region 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.11+8G>C		splice_region intron	N/A	ENSP00000354532.6	P00491
	PNP	ENST00000556293.6	TSL:1	n.130+8G>C		splice_region intron	N/A
	PNP	ENST00000557229.6	TSL:1	n.130+8G>C		splice_region intron	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000628 AC: 1 AN: 159122 AF XY: 0.0000119

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.13e-7 AC: 1 AN: 1402524 Hom.: 0 Cov.: 31 AF XY: 0.00000144 AC XY: 1 AN XY: 692138

African (AFR) AF: 0.00 AC: 0 AN: 31650

American (AMR) AF: 0.00 AC: 0 AN: 35940

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25224

East Asian (EAS) AF: 0.00 AC: 0 AN: 35902

South Asian (SAS) AF: 0.0000126 AC: 1 AN: 79384

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49646

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5284

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1081276

Other (OTH) AF: 0.00 AC: 0 AN: 58218

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Likely 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	-0.53
CADD	Benign	6.7
DANN	Benign	0.71
PhyloP100		0.45
PromoterAI		0.015	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000039
dbscSNV1_RF	Benign	0.0
SpliceAI score (max)		0.050		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: rs1274267125; hg19: chr14-20937702;