rs1476278

Variant names:

• chr17-39679990-C-T
• rs1476278
• NM_033419.5:c.432+4607G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_033419.5(PGAP3):​c.432+4607G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.547 in 151,988 control chromosomes in the GnomAD database, including 24,800 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.55 (24800 hom., cov: 31)
• Consequence: PGAP3 NM_033419.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.27
• Publications: 21 publications found

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]

PGAP3 Gene-Disease associations (from GenCC):

• hyperphosphatasia with intellectual disability syndrome 4

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, ClinGen, Labcorp Genetics (formerly Invitae)
• hyperphosphatasia-intellectual disability syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.676 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_033419.5. 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
	PGAP3	NM_033419.5	MANE Select	c.432+4607G>A		intron	N/A	NP_219487.3
	PGAP3	NM_001291728.2		c.432+4607G>A		intron	N/A	NP_001278657.1	Q96FM1-3
	PGAP3	NM_001291726.2		c.280-5311G>A		intron	N/A	NP_001278655.1	Q96FM1-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PGAP3	ENST00000300658.9	TSL:1 MANE Select	c.432+4607G>A		intron	N/A	ENSP00000300658.4	Q96FM1-1
	PGAP3	ENST00000429199.6	TSL:2	c.432+4607G>A		intron	N/A	ENSP00000415765.2	Q96FM1-3
	PGAP3	ENST00000378011.8	TSL:2	c.280-5311G>A		intron	N/A	ENSP00000367250.4	Q96FM1-2

Frequencies

GnomAD3 genomes AF: 0.547 AC: 83088 AN: 151870 Hom.: 24780 Cov.: 31

Gnomad AFR AF: 0.312

Gnomad AMI AF: 0.742

Gnomad AMR AF: 0.543

Gnomad ASJ AF: 0.675

Gnomad EAS AF: 0.406

Gnomad SAS AF: 0.695

Gnomad FIN AF: 0.691

Gnomad MID AF: 0.656

Gnomad NFE AF: 0.659

Gnomad OTH AF: 0.562

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.547 AC: 83148 AN: 151988 Hom.: 24800 Cov.: 31 AF XY: 0.548 AC XY: 40696 AN XY: 74270

African (AFR) AF: 0.312 AC: 12934 AN: 41454

American (AMR) AF: 0.544 AC: 8311 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.675 AC: 2341 AN: 3470

East Asian (EAS) AF: 0.406 AC: 2100 AN: 5170

South Asian (SAS) AF: 0.696 AC: 3353 AN: 4818

European-Finnish (FIN) AF: 0.691 AC: 7283 AN: 10544

Middle Eastern (MID) AF: 0.647 AC: 189 AN: 292

European-Non Finnish (NFE) AF: 0.659 AC: 44775 AN: 67938

Other (OTH) AF: 0.563 AC: 1187 AN: 2110

Alfa AF: 0.545 Hom.: 5922

Bravo AF: 0.522

Asia WGS AF: 0.581 AC: 2019 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.19
DANN	Benign	0.64
PhyloP100		-1.3
Mutation Taster		=100/0	polymorphism (auto)

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: rs1476278; hg19: chr17-37836243;