17-47941703-G-C

Variant names:

• chr17-47941703-G-C
• rs895290391
• NM_018129.4:c.28G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_018129.4(PNPO):​c.28G>C​(p.Ala10Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000158 in 1,389,186 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. A10A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: PNPO NM_018129.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.11
• Publications: 0 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, ClinGen, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21229166).

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.28G>C	p.Ala10Pro	missense	Exon 1 of 7	NP_060599.1
	PNPO	NM_001436305.1		c.28G>C	p.Ala10Pro	missense	Exon 1 of 6	NP_001423234.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PNPO	ENST00000642017.2	MANE Select	c.28G>C	p.Ala10Pro	missense	Exon 1 of 7	ENSP00000493302.2
	PNPO	ENST00000225573.5	TSL:1	c.28G>C	p.Ala10Pro	missense	Exon 1 of 6	ENSP00000225573.5
	PNPO	ENST00000958514.1		c.28G>C	p.Ala10Pro	missense	Exon 1 of 7	ENSP00000628573.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000158 AC: 22 AN: 1389186 Hom.: 0 Cov.: 31 AF XY: 0.0000190 AC XY: 13 AN XY: 684046

African (AFR) AF: 0.00 AC: 0 AN: 31378

American (AMR) AF: 0.0000281 AC: 1 AN: 35550

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25054

East Asian (EAS) AF: 0.0000282 AC: 1 AN: 35486

South Asian (SAS) AF: 0.00 AC: 0 AN: 78894

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48038

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4436

European-Non Finnish (NFE) AF: 0.0000186 AC: 20 AN: 1073002

Other (OTH) AF: 0.00 AC: 0 AN: 57348

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.0047	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Benign	0.076	T
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.11
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	0.69	N
PhyloP100		3.1
PrimateAI	Benign	0.45	T
PROVEAN	Benign	0.16	N
REVEL	Benign	0.28
Sift	Benign	0.058	T
Sift4G	Benign	0.12	T
Polyphen		0.14	B
Vest4		0.41
MutPred		0.41		Loss of sheet (P = 0.003)
MVP		0.84
MPC		0.75
ClinPred		0.18	T
GERP RS		4.2
PromoterAI		-0.060	Neutral
Varity_R		0.11
gMVP		0.50
Mutation Taster		=93/7	polymorphism

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: rs895290391; hg19: chr17-46019069;