rs104894631

Variant names:

• chr17-47946780-T-C
• rs104894631
• NM_018129.4:c.784T>C

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PS3 PM2 PM4 PP5_Moderate

The NM_018129.4(PNPO):​c.784T>C​(p.Ter262Glnext*?) variant causes a stop lost change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,682 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★). ClinVar reports functional evidence for this variant: "SCV004047196: Expression studies in Chinese hamster ovary cells showed that the stop codon (X262Q) mutation was null activity mutation (Mills et al, 2005).".

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PNPO NM_018129.4 stop_lost
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 7.40
• Publications: 10 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 10 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV004047196: Expression studies in Chinese hamster ovary cells showed that the stop codon (X262Q) mutation was null activity mutation (Mills et al, 2005).
• PM2: Very rare variant in population databases, with high coverage
• PM4: Stoplost variant in NM_018129.4 Downstream stopcodon found after 296 codons.
• PP5: Variant 17-47946780-T-C is Pathogenic according to our data. Variant chr17-47946780-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 6525.Status of the report is criteria_provided_single_submitter, 1 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.784T>C	p.Ter262Glnext*?	stop_lost	Exon 7 of 7	NP_060599.1	Q9NVS9-1
	PNPO	NM_001436305.1		c.655T>C	p.Ter219Glnext*?	stop_lost	Exon 6 of 6	NP_001423234.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PNPO	ENST00000642017.2	MANE Select	c.784T>C	p.Ter262Glnext*?	stop_lost	Exon 7 of 7	ENSP00000493302.2	Q9NVS9-1
	PNPO	ENST00000225573.5	TSL:1	c.655T>C	p.Ter219Glnext*?	stop_lost	Exon 6 of 6	ENSP00000225573.5	Q9NVS9-4
	PNPO	ENST00000958514.1		c.772T>C	p.Ter258Glnext*?	stop_lost	Exon 7 of 7	ENSP00000628573.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461682 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727146

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53358

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5730

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111920

Other (OTH) AF: 0.00 AC: 0 AN: 60384

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
2	-	-	Pyridoxal phosphate-responsive seizures (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.097	D
BayesDel_noAF	Benign	-0.10
CADD	Benign	19
DANN	Benign	0.94
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	0.98	D
PhyloP100		7.4
GERP RS		5.2
Mutation Taster		=2/198	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs104894631; hg19: chr17-46024146;