rs35974730

Variant names:

• chr17-47945929-C-G
• rs35974730
• NM_018129.4:c.486C>G

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_018129.4(PNPO):​c.486C>G​(p.Pro162Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00398 in 1,614,008 control chromosomes in the GnomAD database, including 186 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.019 (94 hom., cov: 32)
  • Exomes 𝑓: 0.0024 (92 hom.)
• Consequence: PNPO NM_018129.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.100
• Publications: 4 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: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.39).
• BP6: Variant 17-47945929-C-G is Benign according to our data. Variant chr17-47945929-C-G is described in ClinVar as Benign. ClinVar VariationId is 129982.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.1 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0624 is higher than 0.05.

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.486C>G	p.Pro162Pro	synonymous	Exon 5 of 7	NP_060599.1	Q9NVS9-1
	PNPO	NM_001436305.1		c.417+317C>G		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.486C>G	p.Pro162Pro	synonymous	Exon 5 of 7	ENSP00000493302.2	Q9NVS9-1
	PNPO	ENST00000225573.5	TSL:1	c.417+317C>G		intron	N/A	ENSP00000225573.5	Q9NVS9-4
	PNPO	ENST00000958514.1		c.486C>G	p.Pro162Pro	synonymous	Exon 5 of 7	ENSP00000628573.1

Frequencies

GnomAD3 genomes AF: 0.0190 AC: 2886 AN: 152180 Hom.: 92 Cov.: 32

Gnomad AFR AF: 0.0643

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00563

Gnomad ASJ AF: 0.0204

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000559

Gnomad OTH AF: 0.0115

GnomAD2 exomes AF: 0.00573 AC: 1441 AN: 251288 AF XY: 0.00462

Gnomad AFR exome AF: 0.0625

Gnomad AMR exome AF: 0.00451

Gnomad ASJ exome AF: 0.0168

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000519

Gnomad OTH exome AF: 0.00619

GnomAD4 exome AF: 0.00241 AC: 3522 AN: 1461710 Hom.: 92 Cov.: 32 AF XY: 0.00220 AC XY: 1597 AN XY: 727150

African (AFR) AF: 0.0639 AC: 2138 AN: 33476

American (AMR) AF: 0.00467 AC: 209 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0171 AC: 448 AN: 26136

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

South Asian (SAS) AF: 0.000162 AC: 14 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53262

Middle Eastern (MID) AF: 0.00520 AC: 30 AN: 5764

European-Non Finnish (NFE) AF: 0.000308 AC: 342 AN: 1112000

Other (OTH) AF: 0.00565 AC: 341 AN: 60392

GnomAD4 genome AF: 0.0190 AC: 2898 AN: 152298 Hom.: 94 Cov.: 32 AF XY: 0.0187 AC XY: 1392 AN XY: 74468

African (AFR) AF: 0.0644 AC: 2678 AN: 41552

American (AMR) AF: 0.00562 AC: 86 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0204 AC: 71 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000559 AC: 38 AN: 68022

Other (OTH) AF: 0.0114 AC: 24 AN: 2114

Alfa AF: 0.00424 Hom.: 12

Bravo AF: 0.0216

Asia WGS AF: 0.00462 AC: 16 AN: 3478

EpiCase AF: 0.000927

EpiControl AF: 0.000771

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	2	Pyridoxal phosphate-responsive seizures (2)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.39
CADD	Benign	10
DANN	Benign	0.74
PhyloP100		-0.10
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=94/6	polymorphism (auto)

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: rs35974730; hg19: chr17-46023295;