22-37659030-A-G

Variant names:

• chr22-37659030-A-G
• rs1933142057
• NM_020315.5:c.248A>G

Variant summary

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

The NM_020315.5(PDXP):​c.248A>G​(p.Glu83Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000000972 in 1,028,292 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E83A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 9.7e-7 (0 hom.)
• Consequence: PDXP NM_020315.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.97
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PDXP	NM_020315.5	c.248A>G	p.Glu83Gly	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.248A>G	p.Glu83Gly	missense_variant	Exon 1 of 2	1	NM_020315.5	ENSP00000215904.6
ENSG00000285304	ENST00000451997.6	c.1501+5157A>G		intron_variant	Intron 16 of 16	2		ENSP00000401076.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 9.72e-7 AC: 1 AN: 1028292 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 489264

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 20300

American (AMR) AF: 0.00 AC: 0 AN: 7578

Ashkenazi Jewish (ASJ) AF: 0.0000859 AC: 1 AN: 11644

East Asian (EAS) AF: 0.00 AC: 0 AN: 19818

South Asian (SAS) AF: 0.00 AC: 0 AN: 25524

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 18562

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2592

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 883476

Other (OTH) AF: 0.00 AC: 0 AN: 38798

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.088	T
BayesDel_noAF	Benign	-0.36
CADD	Pathogenic	27
DANN	Uncertain	0.98
DEOGEN2	Benign	0.043	T
Eigen	Benign	0.17
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.55	T
M_CAP	Pathogenic	0.73	D
MetaRNN	Uncertain	0.66	D
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.6	L
PhyloP100		5.0
PROVEAN	Uncertain	-2.9	D
REVEL	Benign	0.28
Sift	Benign	0.067	T
Sift4G	Uncertain	0.019	D
Polyphen		0.97	D
Vest4		0.41
MutPred		0.60		Gain of MoRF binding (P = 0.0249);
MVP		0.64
MPC		2.5
ClinPred		0.82	D
GERP RS		3.9
PromoterAI		0.00090	Neutral
Varity_R		0.26
gMVP		0.62
Mutation Taster		=13/87	disease causing

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: rs1933142057; hg19: chr22-38055037;