17-47945943-T-C
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Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PM2
The NM_018129.4(PNPO):āc.500T>Cā(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: š 0.000079 ( 0 hom., cov: 32)
Exomes š: 0.00011 ( 0 hom. )
Consequence
PNPO
NM_018129.4 missense
NM_018129.4 missense
Scores
10
4
2
Clinical Significance
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]
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ACMG classification
Classification made for transcript
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: 12AN: 152194Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000175 AC: 44AN: 251324Hom.: 0 AF XY: 0.000199 AC XY: 27AN XY: 135844
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GnomAD4 exome AF: 0.000114 AC: 166AN: 1461734Hom.: 0 Cov.: 32 AF XY: 0.000133 AC XY: 97AN XY: 727172
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GnomAD4 genome AF: 0.0000788 AC: 12AN: 152312Hom.: 0 Cov.: 32 AF XY: 0.0000805 AC XY: 6AN XY: 74488
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:2Uncertain:2Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Benign
T;D;.;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Uncertain
D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
.;H;.;.
MutationTaster
Benign
D;D;D;D
PrimateAI
Uncertain
T
Sift4G
Pathogenic
D;.;.;.
Polyphen
1.0
.;D;.;.
MVP
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at