17-39673351-C-T

Variant names:

• chr17-39673351-C-T
• rs903502
• NM_033419.5:c.695-96G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_033419.5(PGAP3):​c.695-96G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.654 in 1,555,400 control chromosomes in the GnomAD database, including 341,215 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.54 (24877 hom., cov: 32)
  • Exomes 𝑓: 0.67 (316338 hom.)
• Consequence: PGAP3 NM_033419.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.430
• Publications: 33 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BP6: Variant 17-39673351-C-T is Benign according to our data. Variant chr17-39673351-C-T is described in ClinVar as Benign. ClinVar VariationId is 1277582.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.678 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PGAP3	NM_033419.5	MANE Select	c.695-96G>A		intron	N/A	NP_219487.3
	PGAP3	NM_001291728.2		c.632-96G>A		intron	N/A	NP_001278657.1
	PGAP3	NM_001291726.2		c.542-96G>A		intron	N/A	NP_001278655.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PGAP3	ENST00000300658.9	TSL:1 MANE Select	c.695-96G>A		intron	N/A	ENSP00000300658.4
	PGAP3	ENST00000429199.6	TSL:2	c.632-96G>A		intron	N/A	ENSP00000415765.2
	PGAP3	ENST00000378011.8	TSL:2	c.542-96G>A		intron	N/A	ENSP00000367250.4

Frequencies

GnomAD3 genomes AF: 0.541 AC: 82245 AN: 151908 Hom.: 24862 Cov.: 32

Gnomad AFR AF: 0.268

Gnomad AMI AF: 0.791

Gnomad AMR AF: 0.546

Gnomad ASJ AF: 0.679

Gnomad EAS AF: 0.407

Gnomad SAS AF: 0.697

Gnomad FIN AF: 0.695

Gnomad MID AF: 0.652

Gnomad NFE AF: 0.671

Gnomad OTH AF: 0.559

GnomAD4 exome AF: 0.666 AC: 935196 AN: 1403374 Hom.: 316338 Cov.: 27 AF XY: 0.670 AC XY: 466041 AN XY: 695846

African (AFR) AF: 0.265 AC: 8530 AN: 32210

American (AMR) AF: 0.583 AC: 24422 AN: 41886

Ashkenazi Jewish (ASJ) AF: 0.688 AC: 16313 AN: 23722

East Asian (EAS) AF: 0.456 AC: 17713 AN: 38866

South Asian (SAS) AF: 0.735 AC: 58621 AN: 79764

European-Finnish (FIN) AF: 0.692 AC: 32769 AN: 47320

Middle Eastern (MID) AF: 0.726 AC: 3962 AN: 5458

European-Non Finnish (NFE) AF: 0.683 AC: 735286 AN: 1075868

Other (OTH) AF: 0.645 AC: 37580 AN: 58280

GnomAD4 genome AF: 0.541 AC: 82296 AN: 152026 Hom.: 24877 Cov.: 32 AF XY: 0.542 AC XY: 40287 AN XY: 74302

African (AFR) AF: 0.268 AC: 11112 AN: 41456

American (AMR) AF: 0.546 AC: 8340 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.679 AC: 2356 AN: 3470

East Asian (EAS) AF: 0.407 AC: 2097 AN: 5154

South Asian (SAS) AF: 0.698 AC: 3363 AN: 4818

European-Finnish (FIN) AF: 0.695 AC: 7357 AN: 10580

Middle Eastern (MID) AF: 0.639 AC: 188 AN: 294

European-Non Finnish (NFE) AF: 0.671 AC: 45577 AN: 67962

Other (OTH) AF: 0.562 AC: 1186 AN: 2112

Alfa AF: 0.627 Hom.: 39338

Bravo AF: 0.515

Asia WGS AF: 0.595 AC: 2068 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	8.9
DANN	Benign	0.79
PhyloP100		0.43
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs903502; hg19: chr17-37829604; COSMIC: COSV54093480; COSMIC: COSV54093480;