dbSNP rs773614378: PNPO:p.Trp4Cys (chr17-47941687-G-C) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_018129.4(PNPO):c.12G>C(p.Trp4Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000721 in 1,387,088 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. 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: not found (cov: 32)

Exomes 𝑓: 7.2e-7 ( 0 hom. )

Consequence

PNPO
NM_018129.4 missense

Scores

Clinical Significance

Not reported in ClinVar

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

PNPO links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.062046498).

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>C	p.Trp4Cys	missense	Exon 1 of 7	NP_060599.1	Q9NVS9-1
	PNPO	NM_001436305.1		c.12G>C	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>C	p.Trp4Cys	missense	Exon 1 of 7	ENSP00000493302.2	Q9NVS9-1
PNPO	ENST00000225573.5	TSL:1	c.12G>C	p.Trp4Cys	missense	Exon 1 of 6	ENSP00000225573.5	Q9NVS9-4
PNPO	ENST00000958514.1		c.12G>C	p.Trp4Cys	missense	Exon 1 of 7	ENSP00000628573.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000667

AC:

AN:

149974

AF XY:

0.0000125

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

7.21e-7

AC:

AN:

1387088

Hom.:

Cov.:

AF XY:

0.00000146

AC XY:

AN XY:

682684

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31336

American (AMR)

AF:

0.00

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:

0.0000127

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:

0.00

AC:

AN:

57258

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.37

CADD

Benign

(source)

DANN

Benign

0.84

DEOGEN2

Benign

0.077

Eigen

Benign

-0.68

Eigen_PC

Benign

-0.60

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.84

M_CAP

Benign

0.047

MetaRNN

Benign

0.062

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

0.092

GERP RS

3.0

PromoterAI

-0.0060

Neutral

(source)

Varity_R

0.11

gMVP

0.54

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over