chr17-47945943-T-C

Position:

• chr17-47945943-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_018129.4(PNPO):​c.500T>C​(p.Ile167Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00011 in 1,614,046 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000079 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: PNPO NM_018129.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:2 B:1
• Conservation: PhyloP100: 7.77

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 Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a chain Pyridoxine-5'-phosphate oxidase (size 260) in uniprot entity PNPO_HUMAN there are 19 pathogenic changes around while only 2 benign (90%) in NM_018129.4
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PNPO	NM_018129.4	c.500T>C	p.Ile167Thr	missense_variant	5/7	ENST00000642017.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PNPO	ENST00000642017.2	c.500T>C	p.Ile167Thr	missense_variant	5/7		NM_018129.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000788 AC: 12 AN: 152194 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000175 AC: 44 AN: 251324 Hom.: 0 AF XY: 0.000199 AC XY: 27 AN XY: 135844

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.000882

Gnomad FIN exome AF: 0.0000465

Gnomad NFE exome AF: 0.0000703

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000114 AC: 166 AN: 1461734 Hom.: 0 Cov.: 32 AF XY: 0.000133 AC XY: 97 AN XY: 727172

Gnomad4 AFR exome AF: 0.000119

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.000707

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 0.0000683

Gnomad4 OTH exome AF: 0.000215

GnomAD4 genome AF: 0.0000788 AC: 12 AN: 152312 Hom.: 0 Cov.: 32 AF XY: 0.0000805 AC XY: 6 AN XY: 74488

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000101 Hom.: 0

Bravo AF: 0.000106

ExAC AF: 0.000239 AC: 29

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Pyridoxal phosphate-responsive seizures Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 24, 2024	This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 167 of the PNPO protein (p.Ile167Thr). This variant is present in population databases (rs546737191, gnomAD 0.09%). This missense change has been observed in individual(s) with PNPO-related conditions (PMID: 33087887). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 138731). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PNPO protein function with a negative predictive value of 80%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 21, 2023	Variant summary: PNPO c.500T>C (p.Ile167Thr) results in a non-conservative amino acid change in the encoded protein sequence. Four of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00018 in 251324 control chromosomes. This frequency is not higher than estimated for a pathogenic variant in PNPO causing Pyridoxal 5'-Phosphate-Dependent Epilepsy (0.00018 vs 0.0011), allowing no conclusion about variant significance. c.500T>C has been reported in the literature in two homozygous siblings affected with Pyridoxal 5'-Phosphate-Dependent Epilepsy, with evidence of pyridoxine treatment response (Shen_2021). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. One laboratory classified the variant as likely pathogenic, and one laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 10, 2018

The p.I167T variant (also known as c.500T>C), located in coding exon 5 of the PNPO gene, results from a T to C substitution at nucleotide position 500. The isoleucine at codon 167 is replaced by threonine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

PNPO-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 28, 2023

The PNPO c.500T>C variant is predicted to result in the amino acid substitution p.Ile167Thr. This variant has been reported in the homozygous state in siblings with epileptic encephalopathy (Family 4, Table 1, Shen et al. 2021. PubMed ID: 33087887). This variant is reported in 0.088% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/17-46023309-T-C). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 08, 2013

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.61
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Pathogenic	0.39
CADD	Pathogenic	28
DANN	Uncertain	0.98
DEOGEN2	Benign	0.17	T;D;.;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.97	D;D;D;D
M_CAP	Pathogenic	0.43	D
MetaRNN	Uncertain	0.56	D;D;D;D
MetaSVM	Pathogenic	0.80	D
MutationAssessor	Pathogenic	4.1	.;H;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.70	T
Sift4G	Pathogenic	0.0010	D;.;.;.
Polyphen		1.0	.;D;.;.
MVP		0.97
ClinPred		0.36	T
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.85
gMVP		0.73

Splicing

Name	Calibrated prediction	Score	Prediction
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

LitVar

Other links and lift over

dbSNP: rs546737191; hg19: chr17-46023309;