chr17-47944699-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_018129.4(PNPO):c.347G>A(p.Arg116Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.063 in 1,612,942 control chromosomes in the GnomAD database, including 3,593 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. R116R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.050 ( 249 hom., cov: 31)

Exomes 𝑓: 0.064 ( 3344 hom. )

Consequence

PNPO
NM_018129.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 7.79

Publications

50 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.00831601).

BP6

Variant 17-47944699-G-A is Benign according to our data. Variant chr17-47944699-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 129981.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0703 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018129.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PNPO	NM_018129.4	MANE Select	c.347G>A	p.Arg116Gln	missense	Exon 3 of 7	NP_060599.1
	PNPO	NM_001436305.1		c.347G>A	p.Arg116Gln	missense	Exon 3 of 6	NP_001423234.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PNPO	ENST00000642017.2	MANE Select	c.347G>A	p.Arg116Gln	missense	Exon 3 of 7	ENSP00000493302.2
PNPO	ENST00000225573.5	TSL:1	c.347G>A	p.Arg116Gln	missense	Exon 3 of 6	ENSP00000225573.5
PNPO	ENST00000434554.7	TSL:2	c.347G>A	p.Arg116Gln	missense	Exon 3 of 6	ENSP00000399960.3

Frequencies

GnomAD3 genomes

AF:

0.0497

AC:

7560

AN:

152156

Hom.:

248

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0118

Gnomad AMI

AF:

0.0297

Gnomad AMR

AF:

0.0516

Gnomad ASJ

AF:

0.0568

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.0595

Gnomad FIN

AF:

0.0686

Gnomad MID

AF:

0.0633

Gnomad NFE

AF:

0.0720

Gnomad OTH

AF:

0.0612

GnomAD2 exomes

AF:

0.0548

AC:

13779

AN:

251462

AF XY:

0.0575

show subpopulations

Gnomad AFR exome

AF:

0.0110

Gnomad AMR exome

AF:

0.0372

Gnomad ASJ exome

AF:

0.0532

Gnomad EAS exome

AF:

0.000217

Gnomad FIN exome

AF:

0.0651

Gnomad NFE exome

AF:

0.0718

Gnomad OTH exome

AF:

0.0603

GnomAD4 exome

AF:

0.0644

AC:

94131

AN:

1460668

Hom.:

3344

Cov.:

AF XY:

0.0651

AC XY:

47297

AN XY:

726750

show subpopulations

African (AFR)

AF:

0.00860

AC:

288

AN:

33470

American (AMR)

AF:

0.0383

AC:

1712

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.0539

AC:

1409

AN:

26128

East Asian (EAS)

AF:

0.000227

AC:

AN:

39700

South Asian (SAS)

AF:

0.0618

AC:

5329

AN:

86238

European-Finnish (FIN)

AF:

0.0686

AC:

3666

AN:

53408

Middle Eastern (MID)

AF:

0.0742

AC:

427

AN:

5754

European-Non Finnish (NFE)

AF:

0.0702

AC:

77957

AN:

1110904

Other (OTH)

AF:

0.0552

AC:

3334

AN:

60350

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.459

Heterozygous variant carriers

4532

9065

13597

18130

22662

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2746

5492

8238

10984

13730

<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:

0.0496

AC:

7560

AN:

152274

Hom.:

249

Cov.:

AF XY:

0.0481

AC XY:

3578

AN XY:

74458

show subpopulations

African (AFR)

AF:

0.0117

AC:

487

AN:

41552

American (AMR)

AF:

0.0515

AC:

788

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.0568

AC:

197

AN:

3470

East Asian (EAS)

AF:

0.000386

AC:

AN:

5188

South Asian (SAS)

AF:

0.0601

AC:

290

AN:

4822

European-Finnish (FIN)

AF:

0.0686

AC:

728

AN:

10618

Middle Eastern (MID)

AF:

0.0646

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0720

AC:

4896

AN:

68016

Other (OTH)

AF:

0.0597

AC:

126

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

361

722

1084

1445

1806

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

176

264

352

440

<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:

0.0619

Hom.:

1402

Bravo

AF:

0.0453

TwinsUK

AF:

0.0715

AC:

265

ALSPAC

AF:

0.0721

AC:

278

ESP6500AA

AF:

0.0159

AC:

ESP6500EA

AF:

0.0703

AC:

605

ExAC

AF:

0.0557

AC:

6764

Asia WGS

AF:

0.0150

AC:

AN:

3478

EpiCase

AF:

0.0730

EpiControl

AF:

0.0677

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (6)

not provided (2)

Pyridoxal phosphate-responsive seizures (2)

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.14

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.067

Eigen

Uncertain

0.59

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

1.0

MetaRNN

Benign

0.0083

MetaSVM

Benign

-0.78

MutationAssessor

Uncertain

2.3

PhyloP100

7.8

PrimateAI

Uncertain

0.51

PROVEAN

Uncertain

-3.2

REVEL

Uncertain

0.36

Sift

Benign

0.15

Sift4G

Benign

0.093

Polyphen

0.97

Vest4

0.58

MPC

1.1

ClinPred

0.023

GERP RS

5.2

Varity_R

0.65

gMVP

0.62

Mutation Taster

=77/23

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over