17-39672244-G-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BS1_Supporting

The NM_033419.5(PGAP3):c.*559C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00298 in 156,970 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.0029 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0039 (0 hom.)
• Consequence: PGAP3 NM_033419.5 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts P:1 U:3
• Conservation: PhyloP100: -0.680

Genes affected

PGAP3 (HGNC:23719): (post-GPI attachment to proteins phospholipase 3) This gene encodes a glycosylphosphatidylinositol (GPI)-specific phospholipase that primarily localizes to the Golgi apparatus. This ubiquitously expressed gene is predicted to encode a seven-transmembrane protein that removes unsaturated fatty acids from the sn-2 position of GPI. The remodeling of the constituent fatty acids on GPI is thought to be important for the proper association between GPI-anchored proteins and lipid rafts. The tethering of proteins to plasma membranes via posttranslational GPI-anchoring is thought to play a role in protein sorting and trafficking. Mutations in this gene cause an autosomal recessive form of neurologic hyperphosphatasia with cognitive disability (HPMRS4). Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Jul 2017]

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.013018966).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00295 (449/152342) while in subpopulation NFE AF= 0.00481 (327/68032). AF 95% confidence interval is 0.00438. There are 0 homozygotes in gnomad4. There are 212 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PGAP3	NM_033419.5	c.*559C>T		3_prime_UTR_variant	8/8	ENST00000300658.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PGAP3	ENST00000300658.9	c.*559C>T		3_prime_UTR_variant	8/8	1	NM_033419.5	P1

Frequencies

GnomAD3 genomes AF: 0.00295 AC: 449 AN: 152224 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000917

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00157

Gnomad ASJ AF: 0.00374

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00367

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00481

Gnomad OTH AF: 0.000957

GnomAD4 exome AF: 0.00389 AC: 18 AN: 4628 Hom.: 0 Cov.: 0 AF XY: 0.00488 AC XY: 12 AN XY: 2460

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00189

Gnomad4 ASJ exome AF: 0.0333

Gnomad4 EAS exome AF: 0.00581

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00503

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00295 AC: 449 AN: 152342 Hom.: 0 Cov.: 33 AF XY: 0.00285 AC XY: 212 AN XY: 74484

Gnomad4 AFR AF: 0.000914

Gnomad4 AMR AF: 0.00157

Gnomad4 ASJ AF: 0.00374

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00367

Gnomad4 NFE AF: 0.00481

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.00402 Hom.: 0

Bravo AF: 0.00272

TwinsUK AF: 0.00701 AC: 26

ALSPAC AF: 0.00415 AC: 16

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hyperphosphatasia with intellectual disability syndrome 4 Pathogenic:1 Uncertain:3

Uncertain significance, no assertion criteria provided	curation	Reproductive Health Research and Development, BGI Genomics	Jan 06, 2020	NM_033419.3:c.*559C>T in the PGAP3 gene has an allele frequency of 0.006 in European (non-Finnish) subpopulation in the gnomAD database. Two sibblings affected with hyperphosphatasia with mental retardation syndrome, were compound heterozygotes for this variant and a missense c.861G>T mutation (PMID: 27120253). Benign computational verdict because benign predictions from DANN, FATHMM-MKL and MutationTaster. We interpret it as variant of uncertain significance (VUS). ACMG/AMP criteria applied: BP4, PM3. -
Pathogenic, no assertion criteria provided	research	Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin	Mar 01, 2016	Disease causing variant in homozygous or compound heterozygous state. New miRNA binding site is formed and transcript is severly downregulated when the common variant c.*560A>G is also present -
Uncertain significance, criteria provided, single submitter	clinical testing	New York Genome Center	Jun 18, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Centogene AG - the Rare Disease Company	Aug 26, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.76	T
BayesDel_noAF	Benign	-0.86
Cadd	Benign	0.76
Dann	Benign	0.63
FATHMM_MKL	Benign	0.011	N
LIST_S2	Benign	0.32	T
MetaRNN	Benign	0.013	T
MutationTaster	Benign	1.0	N;N;N
Sift4G	Benign	0.32	T
Vest4		0.18
MVP		0.64
GERP RS		-5.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs183208638; hg19: chr17-37828497;