rs4378657

Variant names:

• chr17-47946328-G-A
• rs4378657
• NM_018129.4:c.552G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_018129.4(PNPO):​c.552G>A​(p.Leu184Leu) 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:7
• Conservation: PhyloP100: 0.967
• Publications: 17 publications found

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 Gene-Disease associations (from GenCC):

• pyridoxal phosphate-responsive seizures

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, ClinGen, Labcorp Genetics (formerly Invitae), Orphanet

ENSG00000263798 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 129983.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
PNPO	NM_018129.4	c.552G>A	p.Leu184Leu	synonymous_variant	Exon 6 of 7	ENST00000642017.2	NP_060599.1
PNPO	NM_001436305.1	c.423G>A	p.Leu141Leu	synonymous_variant	Exon 5 of 6		NP_001423234.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PNPO	ENST00000642017.2	c.552G>A	p.Leu184Leu	synonymous_variant	Exon 6 of 7		NM_018129.4	ENSP00000493302.2

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

GnomAD2 exomes AF: 0.0685 AC: 17168 AN: 250688 AF XY: 0.0721

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 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

African (AFR) AF: 0.0278 AC: 931 AN: 33448

American (AMR) AF: 0.0430 AC: 1924 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.0939 AC: 2452 AN: 26100

East Asian (EAS) AF: 0.000252 AC: 10 AN: 39690

South Asian (SAS) AF: 0.0972 AC: 8373 AN: 86150

European-Finnish (FIN) AF: 0.0873 AC: 4658 AN: 53368

Middle Eastern (MID) AF: 0.101 AC: 581 AN: 5756

European-Non Finnish (NFE) AF: 0.0777 AC: 86168 AN: 1108598

Other (OTH) AF: 0.0675 AC: 4066 AN: 60262

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

African (AFR) AF: 0.0316 AC: 1311 AN: 41538

American (AMR) AF: 0.0584 AC: 894 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0985 AC: 342 AN: 3472

East Asian (EAS) AF: 0.000387 AC: 2 AN: 5172

South Asian (SAS) AF: 0.0891 AC: 430 AN: 4828

European-Finnish (FIN) AF: 0.0915 AC: 969 AN: 10588

Middle Eastern (MID) AF: 0.0884 AC: 26 AN: 294

European-Non Finnish (NFE) AF: 0.0812 AC: 5522 AN: 67990

Other (OTH) AF: 0.0711 AC: 150 AN: 2110

Alfa AF: 0.0750 Hom.: 838

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:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

-

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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. -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Pyridoxal phosphate-responsive seizures Benign:2

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Inborn genetic diseases Benign:1

Mar 02, 2016

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.37
CADD	Benign	11
DANN	Benign	0.82
PhyloP100		0.97
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4378657; hg19: chr17-46023694; COSMIC: COSV107309012; COSMIC: COSV107309012;