17-47943332-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_018129.4(PNPO):c.165C>T(p.Ser55Ser) 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

Publications

23 publications found

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 Gene-Disease associations (from GenCC):

pyridoxal phosphate-responsive seizures
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, ClinGen, Labcorp Genetics (formerly Invitae), Orphanet

PNPO links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 129980.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 rank	MANE	Protein	UniProt
PNPO	NM_018129.4 link	c.165C>T	p.Ser55Ser	synonymous_variant	Exon 2 of 7	ENST00000642017.2	NP_060599.1	Q9NVS9-1V9HW45
PNPO	NM_001436305.1 link	c.165C>T	p.Ser55Ser	synonymous_variant	Exon 2 of 6		NP_001423234.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PNPO	ENST00000642017.2 link	c.165C>T	p.Ser55Ser	synonymous_variant	Exon 2 of 7		NM_018129.4	ENSP00000493302.2		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

GnomAD2 exomes

AF:

0.188

AC:

47190

AN:

251398

AF XY:

0.189

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 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

African (AFR)

AF:

0.0674

AC:

2255

AN:

33450

American (AMR)

AF:

0.290

AC:

12942

AN:

44700

Ashkenazi Jewish (ASJ)

AF:

0.206

AC:

5376

AN:

26110

East Asian (EAS)

AF:

0.182

AC:

7221

AN:

39686

South Asian (SAS)

AF:

0.243

AC:

20934

AN:

86206

European-Finnish (FIN)

AF:

0.130

AC:

6927

AN:

53392

Middle Eastern (MID)

AF:

0.170

AC:

980

AN:

5756

European-Non Finnish (NFE)

AF:

0.169

AC:

187402

AN:

1110908

Other (OTH)

AF:

0.173

AC:

10454

AN:

60330

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

9889

19779

29668

39558

49447

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

6862

13724

20586

27448

34310

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.150

AC:

22899

AN:

152168

Hom.:

2007

Cov.:

AF XY:

0.155

AC XY:

11499

AN XY:

74384

show subpopulations

African (AFR)

AF:

0.0688

AC:

2857

AN:

41528

American (AMR)

AF:

0.244

AC:

3735

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.209

AC:

725

AN:

3468

East Asian (EAS)

AF:

0.182

AC:

940

AN:

5176

South Asian (SAS)

AF:

0.252

AC:

1212

AN:

4818

European-Finnish (FIN)

AF:

0.126

AC:

1331

AN:

10586

Middle Eastern (MID)

AF:

0.201

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.171

AC:

11594

AN:

67994

Other (OTH)

AF:

0.147

AC:

310

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

982

1964

2945

3927

4909

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

256

512

768

1024

1280

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.165

Hom.:

9586

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

Jul 15, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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. -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:3

Apr 20, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Pyridoxal phosphate-responsive seizures

Benign:3

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Oct 25, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Benign:1

Jan 08, 2016

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

(source)

DANN

Benign

0.60

PhyloP100

-0.050

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over