NM_018129.4:c.12G>T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_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. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W4S) has been classified 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

Publications

1 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: Orphanet, ClinGen, Labcorp Genetics (formerly Invitae), G2P

PNPO links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PNPO	NM_018129.4	MANE Select	c.12G>T	p.Trp4Cys	missense	Exon 1 of 7	NP_060599.1	Q9NVS9-1
	PNPO	NM_001436305.1		c.12G>T	p.Trp4Cys	missense	Exon 1 of 6	NP_001423234.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PNPO	ENST00000642017.2	MANE Select	c.12G>T	p.Trp4Cys	missense	Exon 1 of 7	ENSP00000493302.2	Q9NVS9-1
PNPO	ENST00000225573.5	TSL:1	c.12G>T	p.Trp4Cys	missense	Exon 1 of 6	ENSP00000225573.5	Q9NVS9-4
PNPO	ENST00000958514.1		c.12G>T	p.Trp4Cys	missense	Exon 1 of 7	ENSP00000628573.1

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

GnomAD2 exomes

AF:

0.00000667

AC:

AN:

149974

AF XY:

0.0000125

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 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

African (AFR)

AF:

0.000351

AC:

AN:

31336

American (AMR)

AF:

0.0000282

AC:

AN:

35496

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24990

East Asian (EAS)

AF:

0.00

AC:

AN:

35424

South Asian (SAS)

AF:

0.00

AC:

AN:

78820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47660

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4314

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1071790

Other (OTH)

AF:

0.0000175

AC:

AN:

57258

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.437

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.000144

AC:

AN:

152254

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

74386

show subpopulations

African (AFR)

AF:

0.000531

AC:

AN:

41460

American (AMR)

AF:

0.00

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5198

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10632

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68052

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.536

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.0000712

Hom.:

Bravo

AF:

0.000132

ExAC

AF:

0.0000104

AC:

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Inborn genetic diseases (1)

Pyridoxal phosphate-responsive seizures (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.37

CADD

Benign

(source)

DANN

Benign

0.85

DEOGEN2

Benign

0.077

Eigen

Benign

-0.68

Eigen_PC

Benign

-0.60

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.84

M_CAP

Benign

0.047

MetaRNN

Benign

0.052

MetaSVM

Benign

-0.95

MutationAssessor

Benign

0.0

PhyloP100

0.65

PrimateAI

Benign

0.34

PROVEAN

Benign

0.21

REVEL

Benign

0.10

Sift

Benign

0.11

Sift4G

Benign

0.16

Polyphen

0.059

Vest4

0.26

MutPred

0.40

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

MVP

0.57

MPC

0.83

ClinPred

0.056

GERP RS

3.0

PromoterAI

-0.084

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.6

Varity_R

0.11

gMVP

0.54

Mutation Taster

=94/6

polymorphism

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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

Computational scores

Splicing

Publications

Other links and lift over