rs267606958

Variant names:

• chr17-47945963-C-T
• rs267606958
• NM_018129.4:c.520C>T

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_018129.4(PNPO):​c.520C>T​(p.Gln174*) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PNPO NM_018129.4 stop_gained
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 5.92
• Publications: 1 publications found

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

ENSG00000263798 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-47945963-C-T is Pathogenic according to our data. Variant chr17-47945963-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 6526.Status of the report is no_assertion_criteria_provided, 0 stars.

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.520C>T	p.Gln174*	stop_gained	Exon 5 of 7	NP_060599.1	Q9NVS9-1
	PNPO	NM_001436305.1		c.417+351C>T		intron	N/A	NP_001423234.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PNPO	ENST00000642017.2	MANE Select	c.520C>T	p.Gln174*	stop_gained	Exon 5 of 7	ENSP00000493302.2	Q9NVS9-1
	PNPO	ENST00000225573.5	TSL:1	c.417+351C>T		intron	N/A	ENSP00000225573.5	Q9NVS9-4
	PNPO	ENST00000958514.1		c.520C>T	p.Gln174*	stop_gained	Exon 5 of 7	ENSP00000628573.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000716 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Pyridoxal phosphate-responsive seizures (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.66
CADD	Pathogenic	41
DANN	Uncertain	1.0
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.98	D
PhyloP100		5.9
GERP RS		5.8
Mutation Taster		=1/199	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs267606958; hg19: chr17-46023329;