Variant rs11079804 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_018129.4(PNPO):c.165C>T(p.Ser55=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.172 in 1,612,706 control chromosomes in the GnomAD database, including 25,431 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.15 ( 2007 hom., cov: 32)

Exomes 𝑓: 0.17 ( 23424 hom. )

Consequence

PNPO
NM_018129.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -0.0500

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.36).

BP6

Variant 17-47943332-C-T is Benign according to our data. Variant chr17-47943332-C-T is described in ClinVar as [Benign]. Clinvar id is 129980.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-47943332-C-T is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-0.05 with no splicing effect.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.24 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PNPO	NM_018129.4 linkuse as main transcript	c.165C>T	p.Ser55=	synonymous_variant	2/7	ENST00000642017.2	NP_060599.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PNPO	ENST00000642017.2 linkuse as main transcript	c.165C>T	p.Ser55=	synonymous_variant	2/7		NM_018129.4	ENSP00000493302	P1	Q9NVS9-1

Frequencies

GnomAD3 genomes

AF:

0.151

AC:

22912

AN:

152048

Hom.:

2010

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0690

Gnomad AMI

AF:

0.150

Gnomad AMR

AF:

0.244

Gnomad ASJ

AF:

0.209

Gnomad EAS

AF:

0.181

Gnomad SAS

AF:

0.253

Gnomad FIN

AF:

0.126

Gnomad MID

AF:

0.203

Gnomad NFE

AF:

0.171

Gnomad OTH

AF:

0.149

GnomAD3 exomes

AF:

0.188

AC:

47190

AN:

251398

Hom.:

5053

AF XY:

0.189

AC XY:

25621

AN XY:

135876

show subpopulations

Gnomad AFR exome

AF:

0.0692

Gnomad AMR exome

AF:

0.298

Gnomad ASJ exome

AF:

0.203

Gnomad EAS exome

AF:

0.186

Gnomad SAS exome

AF:

0.245

Gnomad FIN exome

AF:

0.126

Gnomad NFE exome

AF:

0.167

Gnomad OTH exome

AF:

0.183

GnomAD4 exome

AF:

0.174

AC:

254491

AN:

1460538

Hom.:

23424

Cov.:

AF XY:

0.176

AC XY:

127826

AN XY:

726630

show subpopulations

Gnomad4 AFR exome

AF:

0.0674

Gnomad4 AMR exome

AF:

0.290

Gnomad4 ASJ exome

AF:

0.206

Gnomad4 EAS exome

AF:

0.182

Gnomad4 SAS exome

AF:

0.243

Gnomad4 FIN exome

AF:

0.130

Gnomad4 NFE exome

AF:

0.169

Gnomad4 OTH exome

AF:

0.173

GnomAD4 genome

AF:

0.150

AC:

22899

AN:

152168

Hom.:

2007

Cov.:

AF XY:

0.155

AC XY:

11499

AN XY:

74384

show subpopulations

Gnomad4 AFR

AF:

0.0688

Gnomad4 AMR

AF:

0.244

Gnomad4 ASJ

AF:

0.209

Gnomad4 EAS

AF:

0.182

Gnomad4 SAS

AF:

0.252

Gnomad4 FIN

AF:

0.126

Gnomad4 NFE

AF:

0.171

Gnomad4 OTH

AF:

0.147

Alfa

AF:

0.168

Hom.:

4698

Bravo

AF:

0.156

Asia WGS

AF:

0.227

AC:

787

AN:

3478

EpiCase

AF:

0.174

EpiControl

AF:

0.174

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Jul 15, 2024	This variant is classified as Benign based on local population frequency. This variant was detected in 35% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 33. Only high quality variants are reported. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 20, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Pyridoxal phosphate-responsive seizures

Benign:3

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Oct 25, 2021	- -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 08, 2016

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.36

CADD

Benign

7.6

DANN

Benign

0.60

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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