chr17-39678288-T-C

Variant names:

• chr17-39678288-T-C
• rs12150298
• NM_033419.5:c.433-3609A>G

Variant summary

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

The NM_033419.5(PGAP3):​c.433-3609A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.584 in 152,020 control chromosomes in the GnomAD database, including 26,903 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 0.58 (26903 hom., cov: 32)
• Consequence: PGAP3 NM_033419.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.04
• Publications: 26 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=-0.98).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.677 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PGAP3	NM_033419.5	c.433-3609A>G		intron_variant	Intron 3 of 7	ENST00000300658.9	NP_219487.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PGAP3	ENST00000300658.9	c.433-3609A>G		intron_variant	Intron 3 of 7	1	NM_033419.5	ENSP00000300658.4

Frequencies

GnomAD3 genomes AF: 0.584 AC: 88680 AN: 151902 Hom.: 26872 Cov.: 32

Gnomad AFR AF: 0.437

Gnomad AMI AF: 0.741

Gnomad AMR AF: 0.560

Gnomad ASJ AF: 0.676

Gnomad EAS AF: 0.407

Gnomad SAS AF: 0.696

Gnomad FIN AF: 0.692

Gnomad MID AF: 0.658

Gnomad NFE AF: 0.660

Gnomad OTH AF: 0.584

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

GnomAD4 genome AF: 0.584 AC: 88759 AN: 152020 Hom.: 26903 Cov.: 32 AF XY: 0.583 AC XY: 43345 AN XY: 74302

African (AFR) AF: 0.438 AC: 18135 AN: 41432

American (AMR) AF: 0.560 AC: 8561 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.676 AC: 2342 AN: 3466

East Asian (EAS) AF: 0.407 AC: 2097 AN: 5148

South Asian (SAS) AF: 0.697 AC: 3363 AN: 4824

European-Finnish (FIN) AF: 0.692 AC: 7317 AN: 10580

Middle Eastern (MID) AF: 0.650 AC: 191 AN: 294

European-Non Finnish (NFE) AF: 0.660 AC: 44839 AN: 67966

Other (OTH) AF: 0.586 AC: 1238 AN: 2112

Alfa AF: 0.639 Hom.: 17817

Bravo AF: 0.565

Asia WGS AF: 0.600 AC: 2087 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	0.21
DANN	Benign	0.47
PhyloP100		-2.0
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: rs12150298; hg19: chr17-37834541;