chr17-47941773-A-T

Variant names:

• chr17-47941773-A-T
• rs370243877
• NM_018129.4:c.98A>T

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 14P and 1B. PS3 PP3_Moderate PP5_Very_Strong BS1_Supporting

The NM_018129.4(PNPO):​c.98A>T​(p.Asp33Val) variant causes a missense change. The variant allele was found at a frequency of 0.000221 in 1,567,790 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000242120: Published functional studies demonstrate reduced enzyme activity (Mills et al., 2014)" and additional evidence is available in ClinVar. Synonymous variant affecting the same amino acid position (i.e. D33D) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00023 (0 hom.)
• Consequence: PNPO NM_018129.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:9 O:1
• Conservation: PhyloP100: 4.69
• Publications: 11 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

ACMG classification

Our verdict: Pathogenic. The variant received 13 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000242120: Published functional studies demonstrate reduced enzyme activity (Mills et al., 2014); SCV006098403: PS3:Supporting; SCV000826579: Experimental studies have shown that this missense change affects PNPO function (PMID: 24645144).; SCV000914773: When expressed in HeLa cells, the p.Asp33Val variant protein exhibited a 55% reduction in PNPO activity compared to wildtype (Mills et al. 2004).; SCV002500308: At least one publication reports experimental evidence evaluating an impact on protein function (example, Mills_2014). The most pronounced variant effect results in 44% of normal PNPO activity.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.877
• PP5: Variant 17-47941773-A-T is Pathogenic according to our data. Variant chr17-47941773-A-T is described in ClinVar as Pathogenic. ClinVar VariationId is 206458.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.000232 (329/1415666) while in subpopulation NFE AF = 0.000293 (319/1087976). AF 95% confidence interval is 0.000267. There are 0 homozygotes in GnomAdExome4. There are 139 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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.98A>T	p.Asp33Val	missense	Exon 1 of 7	NP_060599.1	Q9NVS9-1
	PNPO	NM_001436305.1		c.98A>T	p.Asp33Val	missense	Exon 1 of 6	NP_001423234.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PNPO	ENST00000642017.2	MANE Select	c.98A>T	p.Asp33Val	missense	Exon 1 of 7	ENSP00000493302.2	Q9NVS9-1
	PNPO	ENST00000225573.5	TSL:1	c.98A>T	p.Asp33Val	missense	Exon 1 of 6	ENSP00000225573.5	Q9NVS9-4
	PNPO	ENST00000958514.1		c.98A>T	p.Asp33Val	missense	Exon 1 of 7	ENSP00000628573.1

Frequencies

GnomAD3 genomes AF: 0.000118 AC: 18 AN: 152124 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000106 AC: 19 AN: 178538 AF XY: 0.0000940

Gnomad AFR exome AF: 0.0000965

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000247

Gnomad NFE exome AF: 0.000192

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000232 AC: 329 AN: 1415666 Hom.: 0 Cov.: 31 AF XY: 0.000199 AC XY: 139 AN XY: 699970

African (AFR) AF: 0.00 AC: 0 AN: 32406

American (AMR) AF: 0.00 AC: 0 AN: 38432

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25320

East Asian (EAS) AF: 0.00 AC: 0 AN: 37126

South Asian (SAS) AF: 0.00 AC: 0 AN: 80504

European-Finnish (FIN) AF: 0.000120 AC: 6 AN: 49806

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5470

European-Non Finnish (NFE) AF: 0.000293 AC: 319 AN: 1087976

Other (OTH) AF: 0.0000682 AC: 4 AN: 58626

GnomAD4 genome AF: 0.000118 AC: 18 AN: 152124 Hom.: 0 Cov.: 32 AF XY: 0.000135 AC XY: 10 AN XY: 74306

African (AFR) AF: 0.0000724 AC: 3 AN: 41418

American (AMR) AF: 0.0000655 AC: 1 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000176 AC: 12 AN: 68018

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000198 Hom.: 0

Bravo AF: 0.000102

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000234 AC: 2

ExAC AF: 0.0000931 AC: 11

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
5	-	-	Pyridoxal phosphate-responsive seizures (6)
3	-	-	not provided (3)
1	-	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Pathogenic	0.31
CADD	Pathogenic	31
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.52	D
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.92	D
M_CAP	Pathogenic	0.37	D
MetaRNN	Pathogenic	0.88	D
MetaSVM	Uncertain	0.27	D
MutationAssessor	Benign	1.9	L
PhyloP100		4.7
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-6.0	D
REVEL	Pathogenic	0.87
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0080	D
Polyphen		0.99	D
Vest4		0.75
MVP		0.92
MPC		1.6
ClinPred		0.77	D
GERP RS		5.2
PromoterAI		-0.011	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.74
gMVP		0.77
Mutation Taster		=8/92	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs370243877; hg19: chr17-46019139;