rs2517956

Variant names:

• chr17-39687606-G-A
• rs2517956
• NM_033419.5:c.181+228C>T

Your query was ambiguous. Multiple possible variants found:

• chr17-39687606-G-A
• chr17-39687606-G-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.181+228C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.623 in 152,004 control chromosomes in the GnomAD database, including 29,950 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Genomes: 𝑓 0.62 (29950 hom., cov: 32)
• Consequence: PGAP3 NM_033419.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0640
• 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=-0.85).
• BP6: Variant 17-39687606-G-A is Benign according to our data. Variant chr17-39687606-G-A is described in ClinVar as Benign. ClinVar VariationId is 1230219.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.711 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PGAP3	NM_033419.5	c.181+228C>T		intron_variant	Intron 1 of 7	ENST00000300658.9	NP_219487.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PGAP3	ENST00000300658.9	c.181+228C>T		intron_variant	Intron 1 of 7	1	NM_033419.5	ENSP00000300658.4

Frequencies

GnomAD3 genomes AF: 0.623 AC: 94572 AN: 151884 Hom.: 29918 Cov.: 32

Gnomad AFR AF: 0.542

Gnomad AMI AF: 0.741

Gnomad AMR AF: 0.585

Gnomad ASJ AF: 0.697

Gnomad EAS AF: 0.403

Gnomad SAS AF: 0.730

Gnomad FIN AF: 0.704

Gnomad MID AF: 0.703

Gnomad NFE AF: 0.671

Gnomad OTH AF: 0.621

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

GnomAD4 genome AF: 0.623 AC: 94667 AN: 152004 Hom.: 29950 Cov.: 32 AF XY: 0.622 AC XY: 46228 AN XY: 74302

African (AFR) AF: 0.543 AC: 22490 AN: 41420

American (AMR) AF: 0.585 AC: 8939 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.697 AC: 2421 AN: 3472

East Asian (EAS) AF: 0.403 AC: 2079 AN: 5160

South Asian (SAS) AF: 0.731 AC: 3524 AN: 4820

European-Finnish (FIN) AF: 0.704 AC: 7446 AN: 10584

Middle Eastern (MID) AF: 0.690 AC: 203 AN: 294

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

Other (OTH) AF: 0.622 AC: 1314 AN: 2112

Alfa AF: 0.658 Hom.: 127891

Bravo AF: 0.606

Asia WGS AF: 0.629 AC: 2189 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 27, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	3.0
DANN	Benign	0.33
PhyloP100		-0.064
PromoterAI		0.0052	Neutral
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: rs2517956; hg19: chr17-37843859; COSMIC: COSV56131898;