chr17-47941687-G-T

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 4P and 5B. PM1PM2BP4_StrongBS1_Supporting

The NM_018129.4(PNPO):c.12G>T(p.Trp4Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000227 in 1,539,342 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000094 ( 0 hom. )

Consequence

PNPO
NM_018129.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 0.645

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

PM1

In a chain Pyridoxine-5'-phosphate oxidase (size 260) in uniprot entity PNPO_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_018129.4

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.052278936).

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000144 (22/152254) while in subpopulation AFR AF= 0.000531 (22/41460). AF 95% confidence interval is 0.000359. There are 0 homozygotes in gnomad4. There are 11 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PNPO	NM_018129.4 link	c.12G>T	p.Trp4Cys	missense_variant	Exon 1 of 7	ENST00000642017.2	NP_060599.1	Q9NVS9-1V9HW45

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PNPO	ENST00000642017.2 link	c.12G>T	p.Trp4Cys	missense_variant	Exon 1 of 7		NM_018129.4	ENSP00000493302.2		Q9NVS9-1

Frequencies

GnomAD3 genomes

AF:

0.000144

AC:

AN:

152254

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000531

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000667

AC:

AN:

149974

Hom.:

AF XY:

0.0000125

AC XY:

AN XY:

79722

show subpopulations

Gnomad AFR exome

AF:

0.000126

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000937

AC:

AN:

1387088

Hom.:

Cov.:

AF XY:

0.00000732

AC XY:

AN XY:

682684

show subpopulations

Gnomad4 AFR exome

AF:

0.000351

Gnomad4 AMR exome

AF:

0.0000282

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000175

GnomAD4 genome

AF:

0.000144

AC:

AN:

152254

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

74386

show subpopulations

Gnomad4 AFR

AF:

0.000531

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.000132

ExAC

AF:

0.0000104

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

May 20, 2019

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Breakthrough Genomics, Breakthrough Genomics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Inborn genetic diseases

Uncertain:1

Aug 10, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.12G>T (p.W4C) alteration is located in exon 1 (coding exon 1) of the PNPO gene. This alteration results from a G to T substitution at nucleotide position 12, causing the tryptophan (W) at amino acid position 4 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Pyridoxal phosphate-responsive seizures

Uncertain:1

Jun 05, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces tryptophan, which is neutral and slightly polar, with cysteine, which is neutral and slightly polar, at codon 4 of the PNPO protein (p.Trp4Cys). This variant is present in population databases (rs773614378, gnomAD 0.06%). 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: 206439). 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

0.12

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.37

CADD

Benign

DANN

Benign

0.85

DEOGEN2

Benign

0.077

T;.;.

Eigen

Benign

-0.68

Eigen_PC

Benign

-0.60

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.84

T;T;T

M_CAP

Benign

0.047

MetaRNN

Benign

0.052

T;T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

0.0

N;N;N

PrimateAI

Benign

0.34

PROVEAN

Benign

0.21

.;N;N

REVEL

Benign

0.10

Sift

Benign

0.11

.;T;T

Sift4G

Benign

0.16

.;T;T

Polyphen

0.059

B;.;.

Vest4

0.26, 0.26

MutPred

0.40

Loss of MoRF binding (P = 6e-04);Loss of MoRF binding (P = 6e-04);Loss of MoRF binding (P = 6e-04);

MVP

0.57

MPC

0.83

ClinPred

0.056

GERP RS

3.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.6

Varity_R

0.11

gMVP

0.54

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over