rs1565922

Variant names:

• chr17-39674782-A-G
• rs1565922
• NM_033419.5:c.433-103T>C

Your query was ambiguous. Multiple possible variants found:

• chr17-39674782-A-G
• chr17-39674782-A-T

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.433-103T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.673 in 1,156,540 control chromosomes in the GnomAD database, including 265,722 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.62 (30239 hom., cov: 30)
  • Exomes 𝑓: 0.68 (235483 hom.)
• Consequence: PGAP3 NM_033419.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.397
• Publications: 38 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=-0.91).
• BP6: Variant 17-39674782-A-G is Benign according to our data. Variant chr17-39674782-A-G is described in ClinVar as Benign. ClinVar VariationId is 1282412.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.715 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.433-103T>C		intron	N/A	NP_219487.3
	PGAP3	NM_001291728.2		c.433-728T>C		intron	N/A	NP_001278657.1	Q96FM1-3
	PGAP3	NM_001291726.2		c.280-103T>C		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.433-103T>C		intron	N/A	ENSP00000300658.4	Q96FM1-1
	PGAP3	ENST00000429199.6	TSL:2	c.433-728T>C		intron	N/A	ENSP00000415765.2	Q96FM1-3
	PGAP3	ENST00000378011.8	TSL:2	c.280-103T>C		intron	N/A	ENSP00000367250.4	Q96FM1-2

Frequencies

GnomAD3 genomes AF: 0.623 AC: 94450 AN: 151680 Hom.: 30210 Cov.: 30

Gnomad AFR AF: 0.501

Gnomad AMI AF: 0.815

Gnomad AMR AF: 0.583

Gnomad ASJ AF: 0.699

Gnomad EAS AF: 0.409

Gnomad SAS AF: 0.734

Gnomad FIN AF: 0.721

Gnomad MID AF: 0.688

Gnomad NFE AF: 0.692

Gnomad OTH AF: 0.619

GnomAD4 exome AF: 0.681 AC: 684043 AN: 1004742 Hom.: 235483 AF XY: 0.685 AC XY: 346719 AN XY: 506310

African (AFR) AF: 0.495 AC: 11569 AN: 23392

American (AMR) AF: 0.584 AC: 18417 AN: 31544

Ashkenazi Jewish (ASJ) AF: 0.700 AC: 14087 AN: 20122

East Asian (EAS) AF: 0.462 AC: 15410 AN: 33346

South Asian (SAS) AF: 0.762 AC: 49073 AN: 64408

European-Finnish (FIN) AF: 0.714 AC: 28572 AN: 40020

Middle Eastern (MID) AF: 0.763 AC: 3639 AN: 4772

European-Non Finnish (NFE) AF: 0.691 AC: 513340 AN: 742448

Other (OTH) AF: 0.670 AC: 29936 AN: 44690

GnomAD4 genome AF: 0.623 AC: 94534 AN: 151798 Hom.: 30239 Cov.: 30 AF XY: 0.622 AC XY: 46140 AN XY: 74192

African (AFR) AF: 0.501 AC: 20724 AN: 41362

American (AMR) AF: 0.583 AC: 8910 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.699 AC: 2422 AN: 3464

East Asian (EAS) AF: 0.409 AC: 2102 AN: 5138

South Asian (SAS) AF: 0.736 AC: 3532 AN: 4802

European-Finnish (FIN) AF: 0.721 AC: 7609 AN: 10558

Middle Eastern (MID) AF: 0.675 AC: 197 AN: 292

European-Non Finnish (NFE) AF: 0.692 AC: 46986 AN: 67890

Other (OTH) AF: 0.620 AC: 1310 AN: 2112

Alfa AF: 0.676 Hom.: 56384

Bravo AF: 0.603

Asia WGS AF: 0.631 AC: 2194 AN: 3476

ClinVar

ClinVar submissions

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	-0.91
CADD	Benign	0.39
DANN	Benign	0.53
PhyloP100		-0.40
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: rs1565922; hg19: chr17-37831035; COSMIC: COSV54092915; COSMIC: COSV54092915;