rs765314515

Positions:

• chr17-47941766-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_018129.4(PNPO):​c.91G>C​(p.Ala31Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000142 in 1,413,246 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PNPO NM_018129.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.29

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 2 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
• BP4: Computational evidence support a benign effect (MetaRNN=0.0981313).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PNPO	NM_018129.4	c.91G>C	p.Ala31Pro	missense_variant	1/7	ENST00000642017.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PNPO	ENST00000642017.2	c.91G>C	p.Ala31Pro	missense_variant	1/7		NM_018129.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000114 AC: 2 AN: 175092 Hom.: 0 AF XY: 0.0000107 AC XY: 1 AN XY: 93558

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000736

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: 0.00000142 AC: 2 AN: 1413246 Hom.: 0 Cov.: 31 AF XY: 0.00000143 AC XY: 1 AN XY: 698512

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000527

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: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ExAC AF: 0.0000170 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Pyridoxal phosphate-responsive seizures Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Feb 21, 2020

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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with PNPO-related disease. ClinVar contains an entry for this variant (Variation ID: 409831). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This sequence change replaces alanine with proline at codon 31 of the PNPO protein (p.Ala31Pro). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and proline. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Benign	0.13	T;.;.;.
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.61
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.82	T;T;T;T
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.098	T;T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.90	L;L;L;.
MutationTaster	Benign	1.0	D;N;N;N
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.4	.;N;N;.
REVEL	Benign	0.082
Sift	Benign	0.28	.;T;T;.
Sift4G	Benign	0.27	.;T;T;.
Polyphen		0.066	B;.;.;.
Vest4		0.28, 0.28
MutPred		0.40		Gain of disorder (P = 0.0398);Gain of disorder (P = 0.0398);Gain of disorder (P = 0.0398);.;
MVP		0.82
MPC		0.73
ClinPred		0.084	T
GERP RS		3.3
Varity_R		0.13
gMVP		0.42

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs765314515; hg19: chr17-46019132;