22-37658846-G-A

Variant names:

• chr22-37658846-G-A
• rs780427943
• NM_020315.5:c.64G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_020315.5(PDXP):​c.64G>A​(p.Val22Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000176 in 1,206,446 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V22D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00010 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00019 (0 hom.)
• Consequence: PDXP NM_020315.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.273
• Publications: 0 publications found

Genes affected

PDXP (HGNC:30259): (pyridoxal phosphatase) Pyridoxal 5-prime-phosphate (PLP) is the active form of vitamin B6 that acts as a coenzyme in maintaining biochemical homeostasis. The preferred degradation route from PLP to 4-pyridoxic acid involves the dephosphorylation of PLP by PDXP (Jang et al., 2003 [PubMed 14522954]).[supplied by OMIM, Mar 2008]

ENSG00000285304 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.076075196).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PDXP	NM_020315.5	c.64G>A	p.Val22Ile	missense_variant	Exon 1 of 2	ENST00000215904.7	NP_064711.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PDXP	ENST00000215904.7	c.64G>A	p.Val22Ile	missense_variant	Exon 1 of 2	1	NM_020315.5	ENSP00000215904.6
ENSG00000285304	ENST00000451997.6	c.1501+4973G>A		intron_variant	Intron 16 of 16	2		ENSP00000401076.2

Frequencies

GnomAD3 genomes AF: 0.000100 AC: 15 AN: 149572 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000664

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000194

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00 AC: 0 AN: 23758 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000186 AC: 197 AN: 1056874 Hom.: 0 Cov.: 31 AF XY: 0.000190 AC XY: 95 AN XY: 500980

African (AFR) AF: 0.00 AC: 0 AN: 22358

American (AMR) AF: 0.00 AC: 0 AN: 7908

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 12360

East Asian (EAS) AF: 0.00 AC: 0 AN: 24402

South Asian (SAS) AF: 0.00 AC: 0 AN: 21942

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 20806

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2686

European-Non Finnish (NFE) AF: 0.000215 AC: 194 AN: 903312

Other (OTH) AF: 0.0000730 AC: 3 AN: 41100

GnomAD4 genome AF: 0.000100 AC: 15 AN: 149572 Hom.: 0 Cov.: 32 AF XY: 0.000110 AC XY: 8 AN XY: 72922

African (AFR) AF: 0.00 AC: 0 AN: 41092

American (AMR) AF: 0.0000664 AC: 1 AN: 15052

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3436

East Asian (EAS) AF: 0.00 AC: 0 AN: 5108

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9772

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.000194 AC: 13 AN: 67022

Other (OTH) AF: 0.00 AC: 0 AN: 2056

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.000125

ExAC AF: 0.0000220 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 08, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.64G>A (p.V22I) alteration is located in exon 1 (coding exon 1) of the PDXP gene. This alteration results from a G to A substitution at nucleotide position 64, causing the valine (V) at amino acid position 22 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.014	T
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.42
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.52	T
M_CAP	Pathogenic	0.34	D
MetaRNN	Benign	0.076	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.55	N
PhyloP100		0.27
PROVEAN	Benign	-0.12	N
REVEL	Benign	0.015
Sift	Benign	0.28	T
Sift4G	Benign	0.44	T
Polyphen		0.0010	B
Vest4		0.15
MutPred		0.64		Loss of MoRF binding (P = 0.1086);
MVP		0.088
MPC		1.5
ClinPred		0.087	T
GERP RS		1.9
PromoterAI		0.083	Neutral
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.7
Varity_R		0.055
gMVP		0.18
Mutation Taster		=75/25	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: rs780427943; hg19: chr22-38054853;