rs138727329

Variant names:

• chr17-47945987-G-A
• rs138727329
• NM_018129.4:c.544G>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 2P and 7B. PM1 BP4_Moderate BP6 BS1

The NM_018129.4(PNPO):​c.544G>A​(p.Glu182Lys) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000273 in 1,613,798 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000028 (0 hom.)
• Consequence: PNPO NM_018129.4 missense, splice_region
• Scores: Splicing: ADA: 0.04397
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 6.10

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]

ENSG00000263798 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• PM1: In a chain Pyridoxine-5'-phosphate oxidase (size 260) in uniprot entity PNPO_HUMAN there are 23 pathogenic changes around while only 2 benign (92%) in NM_018129.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.09280807).
• BP6: Variant 17-47945987-G-A is Benign according to our data. Variant chr17-47945987-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 206459.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=1}.
• BS1: Variant frequency is greater than expected in population eas. GnomAdExome4 allele frequency = 0.0000281 (41/1461462) while in subpopulation EAS AF = 0.000403 (16/39700). AF 95% confidence interval is 0.000252. There are 0 homozygotes in GnomAdExome4. There are 20 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position FAILED quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PNPO	NM_018129.4	c.544G>A	p.Glu182Lys	missense_variant, splice_region_variant	Exon 5 of 7	ENST00000642017.2	NP_060599.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PNPO	ENST00000642017.2	c.544G>A	p.Glu182Lys	missense_variant, splice_region_variant	Exon 5 of 7		NM_018129.4	ENSP00000493302.2

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152218 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000111 AC: 28 AN: 251156 AF XY: 0.0000958

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00125

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000281 AC: 41 AN: 1461462 Hom.: 0 Cov.: 32 AF XY: 0.0000275 AC XY: 20 AN XY: 727026

Gnomad4 AFR exome AF: 0.0000299 AC: 1 AN: 33474

Gnomad4 AMR exome AF: 0.00 AC: 0 AN: 44722

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 26136

Gnomad4 EAS exome AF: 0.000403 AC: 16 AN: 39700

Gnomad4 SAS exome AF: 0.00 AC: 0 AN: 86240

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 53154

Gnomad4 NFE exome AF: 0.0000216 AC: 24 AN: 1112004

Gnomad4 Remaining exome AF: 0.00 AC: 0 AN: 60376

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152336 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74484

Gnomad4 AFR AF: 0.00 AC: 0 AN: 0

Gnomad4 AMR AF: 0.00 AC: 0 AN: 0

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.000386 AC: 0.0003861 AN: 0.0003861

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.00 AC: 0 AN: 0

Gnomad4 OTH AF: 0.00 AC: 0 AN: 0

Alfa AF: 0.0000439 Hom.: 0

Bravo AF: 0.0000378

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000107 AC: 13

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Nov 14, 2018

Athena Diagnostics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 09, 2015

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The E182K variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The E182K variant was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. The E182K variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size, and/or other properties. This substitution occurs at a position where amino acids with similar properties to Glutamic acid are tolerated across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. -

Pyridoxal phosphate-responsive seizures Uncertain:1

Oct 23, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 182 of the PNPO protein (p.Glu182Lys). This variant is present in population databases (rs138727329, gnomAD 0.1%). This variant has not been reported in the literature in individuals affected with PNPO-related conditions. ClinVar contains an entry for this variant (Variation ID: 206459). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.24
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.031	T;T;.;.
Eigen	Benign	-0.095
Eigen_PC	Benign	0.062
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.84	T;D;T;T
M_CAP	Benign	0.072	D
MetaRNN	Benign	0.093	T;T;T;T
MetaSVM	Benign	-0.60	T
MutationAssessor	Benign	1.7	.;L;.;.
PrimateAI	Uncertain	0.60	T
Sift4G	Benign	0.15	T;.;.;.
Polyphen		0.28	.;B;.;.
MVP		0.78
ClinPred		0.14	T
GERP RS		4.8
Varity_R		0.33
gMVP		0.31
Mutation Taster		=56/44	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.044
dbscSNV1_RF	Benign	0.35
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: rs138727329; hg19: chr17-46023353;