Variant rs796052872 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_018129.4(PNPO):c.448_451del(p.Pro150ArgfsTer27) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,613,726 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

PNPO
NM_018129.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 7.77

Variant links:

Genes affected

PNPO (HGNC:30260): (pyridoxamine 5'-phosphate oxidase) The enzyme encoded by this gene catalyzes the terminal, rate-limiting step in the synthesis of pyridoxal 5'-phosphate, also known as vitamin B6. Vitamin B6 is a required co-factor for enzymes involved in both homocysteine metabolism and synthesis of neurotransmitters such as catecholamine. Mutations in this gene result in pyridoxamine 5'-phosphate oxidase (PNPO) deficiency, a form of neonatal epileptic encephalopathy. [provided by RefSeq, Oct 2008]

PNPO links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 17-47945887-ACTGC-A is Pathogenic according to our data. Variant chr17-47945887-ACTGC-A is described in ClinVar as [Pathogenic]. Clinvar id is 206460.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PNPO	NM_018129.4 linkuse as main transcript	c.448_451del	p.Pro150ArgfsTer27	frameshift_variant	5/7	ENST00000642017.2	NP_060599.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PNPO	ENST00000642017.2 linkuse as main transcript	c.448_451del	p.Pro150ArgfsTer27	frameshift_variant	5/7		NM_018129.4	ENSP00000493302	P1	Q9NVS9-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

251026

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135698

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000217

Gnomad SAS 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:

0.00000342

AC:

AN:

1461554

Hom.:

AF XY:

0.00000275

AC XY:

AN XY:

727060

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000126

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152172

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74350

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000151

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Pyridoxal phosphate-responsive seizures

Pathogenic:2

Likely pathogenic, no assertion criteria provided	clinical testing	Knight Diagnostic Laboratories, Oregon Health and Sciences University	Mar 12, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 19, 2023	This sequence change creates a premature translational stop signal (p.Pro150Argfs*27) in the PNPO gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PNPO are known to be pathogenic (PMID: 15772097, 24645144). This variant is present in population databases (rs775105142, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with clinical features of pyridoxal 5'-phosphate-dependent epilepsy (PMID: 28349276, 29588952). ClinVar contains an entry for this variant (Variation ID: 206460). For these reasons, this variant has been classified as Pathogenic. -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Nov 07, 2014

c.448_451delCCTG: p.Pro150ArgfsX27 in exon 5 in the PNPO gene (NM_018129.3). The normal sequence with the bases that are deleted in braces is: ACTG{CCTG}AGGA. The maternally inherited c.448_451delCCTG mutation in the PNPO gene has not been reported previously as a disease-causing mutation nor as a benign polymorphism, to our knowledge. The c.448_451delCCTG mutation causes a frameshift starting with codon Proline 150, changes this amino acid to a Arginine residue and creates a premature Stop codon at position 27 of the new reading frame, denoted p.Pro150ArgfsX27. This mutation is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.448_451delCCTG mutation was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret c.448_451delCCTG as a disease-causing mutation. This variant has been observed to be maternally inherited The variant is found in PNPO, panel(s). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over