rs4378657

Positions:

• chr17-47946328-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_018129.4(PNPO):​c.552G>A​(p.Leu184=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0738 in 1,610,284 control chromosomes in the GnomAD database, including 4,933 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.064 (366 hom., cov: 32)
  • Exomes 𝑓: 0.075 (4567 hom.)
• Consequence: PNPO NM_018129.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.967

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]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.37).
• BP6: Variant 17-47946328-G-A is Benign according to our data. Variant chr17-47946328-G-A is described in ClinVar as [Benign]. Clinvar id is 129983.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-47946328-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.967 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0821 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PNPO	NM_018129.4	c.552G>A	p.Leu184=	synonymous_variant	6/7	ENST00000642017.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PNPO	ENST00000642017.2	c.552G>A	p.Leu184=	synonymous_variant	6/7		NM_018129.4	P1

Frequencies

GnomAD3 genomes AF: 0.0636 AC: 9668 AN: 152080 Hom.: 365 Cov.: 32

Gnomad AFR AF: 0.0315

Gnomad AMI AF: 0.0297

Gnomad AMR AF: 0.0585

Gnomad ASJ AF: 0.0985

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.0886

Gnomad FIN AF: 0.0915

Gnomad MID AF: 0.0854

Gnomad NFE AF: 0.0812

Gnomad OTH AF: 0.0728

GnomAD3 exomes AF: 0.0685 AC: 17168 AN: 250688 Hom.: 738 AF XY: 0.0721 AC XY: 9775 AN XY: 135578

Gnomad AFR exome AF: 0.0311

Gnomad AMR exome AF: 0.0413

Gnomad ASJ exome AF: 0.0935

Gnomad EAS exome AF: 0.000272

Gnomad SAS exome AF: 0.0947

Gnomad FIN exome AF: 0.0864

Gnomad NFE exome AF: 0.0803

Gnomad OTH exome AF: 0.0733

GnomAD4 exome AF: 0.0749 AC: 109163 AN: 1458086 Hom.: 4567 Cov.: 30 AF XY: 0.0764 AC XY: 55453 AN XY: 725534

Gnomad4 AFR exome AF: 0.0278

Gnomad4 AMR exome AF: 0.0430

Gnomad4 ASJ exome AF: 0.0939

Gnomad4 EAS exome AF: 0.000252

Gnomad4 SAS exome AF: 0.0972

Gnomad4 FIN exome AF: 0.0873

Gnomad4 NFE exome AF: 0.0777

Gnomad4 OTH exome AF: 0.0675

GnomAD4 genome AF: 0.0636 AC: 9673 AN: 152198 Hom.: 366 Cov.: 32 AF XY: 0.0628 AC XY: 4676 AN XY: 74416

Gnomad4 AFR AF: 0.0316

Gnomad4 AMR AF: 0.0584

Gnomad4 ASJ AF: 0.0985

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.0891

Gnomad4 FIN AF: 0.0915

Gnomad4 NFE AF: 0.0812

Gnomad4 OTH AF: 0.0711

Alfa AF: 0.0761 Hom.: 634

Bravo AF: 0.0576

Asia WGS AF: 0.0240 AC: 83 AN: 3478

EpiCase AF: 0.0836

EpiControl AF: 0.0769

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Pyridoxal phosphate-responsive seizures Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 02, 2016

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.37
CADD	Benign	11
DANN	Benign	0.82

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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

Other links and lift over

dbSNP: rs4378657; hg19: chr17-46023694;