rs2247862

Variant names:

• chr17-39672876-A-G
• rs2247862
• NM_033419.5:c.900-10T>C

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.900-10T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.686 in 1,612,766 control chromosomes in the GnomAD database, including 383,224 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.64 (31637 hom., cov: 33)
  • Exomes 𝑓: 0.69 (351587 hom.)
• Consequence: PGAP3 NM_033419.5 intron
• Scores: Splicing: ADA: 0.0002155
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.73
• Publications: 27 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: Labcorp Genetics (formerly Invitae), ClinGen, G2P
• 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=-0.81).
• BP6: Variant 17-39672876-A-G is Benign according to our data. Variant chr17-39672876-A-G is described in ClinVar as Benign. ClinVar VariationId is 1268616.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.718 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.900-10T>C		intron	N/A	NP_219487.3
	PGAP3	NM_001291728.2		c.837-10T>C		intron	N/A	NP_001278657.1	Q96FM1-3
	PGAP3	NM_001291726.2		c.747-10T>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.900-10T>C		intron	N/A	ENSP00000300658.4	Q96FM1-1
	PGAP3	ENST00000429199.6	TSL:2	c.837-10T>C		intron	N/A	ENSP00000415765.2	Q96FM1-3
	PGAP3	ENST00000378011.8	TSL:2	c.747-10T>C		intron	N/A	ENSP00000367250.4	Q96FM1-2

Frequencies

GnomAD3 genomes AF: 0.639 AC: 97147 AN: 151920 Hom.: 31609 Cov.: 33

Gnomad AFR AF: 0.556

Gnomad AMI AF: 0.812

Gnomad AMR AF: 0.592

Gnomad ASJ AF: 0.699

Gnomad EAS AF: 0.409

Gnomad SAS AF: 0.737

Gnomad FIN AF: 0.721

Gnomad MID AF: 0.699

Gnomad NFE AF: 0.693

Gnomad OTH AF: 0.629

GnomAD2 exomes AF: 0.666 AC: 166086 AN: 249254 AF XY: 0.678

Gnomad AFR exome AF: 0.555

Gnomad AMR exome AF: 0.610

Gnomad ASJ exome AF: 0.713

Gnomad EAS exome AF: 0.379

Gnomad FIN exome AF: 0.725

Gnomad NFE exome AF: 0.703

Gnomad OTH exome AF: 0.682

GnomAD4 exome AF: 0.691 AC: 1009671 AN: 1460730 Hom.: 351587 Cov.: 49 AF XY: 0.694 AC XY: 504628 AN XY: 726714

African (AFR) AF: 0.553 AC: 18511 AN: 33458

American (AMR) AF: 0.606 AC: 27047 AN: 44668

Ashkenazi Jewish (ASJ) AF: 0.708 AC: 18493 AN: 26120

East Asian (EAS) AF: 0.455 AC: 18052 AN: 39668

South Asian (SAS) AF: 0.770 AC: 66382 AN: 86206

European-Finnish (FIN) AF: 0.719 AC: 38384 AN: 53366

Middle Eastern (MID) AF: 0.770 AC: 4415 AN: 5732

European-Non Finnish (NFE) AF: 0.699 AC: 777206 AN: 1111156

Other (OTH) AF: 0.682 AC: 41181 AN: 60356

GnomAD4 genome AF: 0.640 AC: 97237 AN: 152036 Hom.: 31637 Cov.: 33 AF XY: 0.639 AC XY: 47457 AN XY: 74322

African (AFR) AF: 0.557 AC: 23060 AN: 41420

American (AMR) AF: 0.593 AC: 9053 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.699 AC: 2427 AN: 3470

East Asian (EAS) AF: 0.409 AC: 2114 AN: 5164

South Asian (SAS) AF: 0.738 AC: 3560 AN: 4824

European-Finnish (FIN) AF: 0.721 AC: 7644 AN: 10604

Middle Eastern (MID) AF: 0.684 AC: 201 AN: 294

European-Non Finnish (NFE) AF: 0.693 AC: 47107 AN: 67960

Other (OTH) AF: 0.631 AC: 1332 AN: 2112

Alfa AF: 0.661 Hom.: 13254

Bravo AF: 0.622

Asia WGS AF: 0.634 AC: 2205 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Hyperphosphatasia with intellectual disability syndrome 4 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.27
DANN	Benign	0.71
PhyloP100		-1.7
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00022
dbscSNV1_RF	Benign	0.0080
SpliceAI score (max)		0.080		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: rs2247862; hg19: chr17-37829129; COSMIC: COSV54092907; COSMIC: COSV54092907;