chr17-47943332-C-T

Variant names:

• chr17-47943332-C-T
• rs11079804
• NM_018129.4:c.165C>T

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.165C>T​(p.Ser55Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.172 in 1,612,706 control chromosomes in the GnomAD database, including 25,431 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (2007 hom., cov: 32)
  • Exomes 𝑓: 0.17 (23424 hom.)
• Consequence: PNPO NM_018129.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.0500
• Publications: 23 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: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.36).
• BP6: Variant 17-47943332-C-T is Benign according to our data. Variant chr17-47943332-C-T is described in ClinVar as Benign. ClinVar VariationId is 129980.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.05 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.24 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.165C>T	p.Ser55Ser	synonymous	Exon 2 of 7	NP_060599.1
	PNPO	NM_001436305.1		c.165C>T	p.Ser55Ser	synonymous	Exon 2 of 6	NP_001423234.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PNPO	ENST00000642017.2	MANE Select	c.165C>T	p.Ser55Ser	synonymous	Exon 2 of 7	ENSP00000493302.2
	PNPO	ENST00000225573.5	TSL:1	c.165C>T	p.Ser55Ser	synonymous	Exon 2 of 6	ENSP00000225573.5
	PNPO	ENST00000958514.1		c.165C>T	p.Ser55Ser	synonymous	Exon 2 of 7	ENSP00000628573.1

Frequencies

GnomAD3 genomes AF: 0.151 AC: 22912 AN: 152048 Hom.: 2010 Cov.: 32

Gnomad AFR AF: 0.0690

Gnomad AMI AF: 0.150

Gnomad AMR AF: 0.244

Gnomad ASJ AF: 0.209

Gnomad EAS AF: 0.181

Gnomad SAS AF: 0.253

Gnomad FIN AF: 0.126

Gnomad MID AF: 0.203

Gnomad NFE AF: 0.171

Gnomad OTH AF: 0.149

GnomAD2 exomes AF: 0.188 AC: 47190 AN: 251398 AF XY: 0.189

Gnomad AFR exome AF: 0.0692

Gnomad AMR exome AF: 0.298

Gnomad ASJ exome AF: 0.203

Gnomad EAS exome AF: 0.186

Gnomad FIN exome AF: 0.126

Gnomad NFE exome AF: 0.167

Gnomad OTH exome AF: 0.183

GnomAD4 exome AF: 0.174 AC: 254491 AN: 1460538 Hom.: 23424 Cov.: 32 AF XY: 0.176 AC XY: 127826 AN XY: 726630

African (AFR) AF: 0.0674 AC: 2255 AN: 33450

American (AMR) AF: 0.290 AC: 12942 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.206 AC: 5376 AN: 26110

East Asian (EAS) AF: 0.182 AC: 7221 AN: 39686

South Asian (SAS) AF: 0.243 AC: 20934 AN: 86206

European-Finnish (FIN) AF: 0.130 AC: 6927 AN: 53392

Middle Eastern (MID) AF: 0.170 AC: 980 AN: 5756

European-Non Finnish (NFE) AF: 0.169 AC: 187402 AN: 1110908

Other (OTH) AF: 0.173 AC: 10454 AN: 60330

GnomAD4 genome AF: 0.150 AC: 22899 AN: 152168 Hom.: 2007 Cov.: 32 AF XY: 0.155 AC XY: 11499 AN XY: 74384

African (AFR) AF: 0.0688 AC: 2857 AN: 41528

American (AMR) AF: 0.244 AC: 3735 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.209 AC: 725 AN: 3468

East Asian (EAS) AF: 0.182 AC: 940 AN: 5176

South Asian (SAS) AF: 0.252 AC: 1212 AN: 4818

European-Finnish (FIN) AF: 0.126 AC: 1331 AN: 10586

Middle Eastern (MID) AF: 0.201 AC: 59 AN: 294

European-Non Finnish (NFE) AF: 0.171 AC: 11594 AN: 67994

Other (OTH) AF: 0.147 AC: 310 AN: 2110

Alfa AF: 0.165 Hom.: 9586

Bravo AF: 0.156

Asia WGS AF: 0.227 AC: 787 AN: 3478

EpiCase AF: 0.174

EpiControl AF: 0.174

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	3	Pyridoxal phosphate-responsive seizures (3)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.36
CADD	Benign	7.6
DANN	Benign	0.60
PhyloP100		-0.050
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs11079804; hg19: chr17-46020698; COSMIC: COSV56666459; COSMIC: COSV56666459;