rs907087

Variant names:

• chr17-39672534-G-A
• rs907087
• NM_033419.5:c.*269C>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.*269C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.68 in 544,726 control chromosomes in the GnomAD database, including 127,690 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.66 (33742 hom., cov: 32)
  • Exomes 𝑓: 0.69 (93948 hom.)
• Consequence: PGAP3 NM_033419.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.13
• 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: 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 (MetaRNN=0.0045864284).
• BP6: Variant 17-39672534-G-A is Benign according to our data. Variant chr17-39672534-G-A is described in ClinVar as Benign. ClinVar VariationId is 1239136.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.716 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.*269C>T		3_prime_UTR	Exon 8 of 8	NP_219487.3
	PGAP3	NM_001291728.2		c.*269C>T		3_prime_UTR	Exon 7 of 7	NP_001278657.1	Q96FM1-3
	PGAP3	NM_001291726.2		c.*269C>T		3_prime_UTR	Exon 7 of 7	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.*269C>T		3_prime_UTR	Exon 8 of 8	ENSP00000300658.4	Q96FM1-1
	PGAP3	ENST00000619169.4	TSL:2	c.158C>T	p.Ala53Val	missense	Exon 5 of 5	ENSP00000478028.1	A0A087WTP0
	PGAP3	ENST00000378011.8	TSL:2	c.*269C>T		3_prime_UTR	Exon 7 of 7	ENSP00000367250.4	Q96FM1-2

Frequencies

GnomAD3 genomes AF: 0.663 AC: 100655 AN: 151918 Hom.: 33700 Cov.: 32

Gnomad AFR AF: 0.637

Gnomad AMI AF: 0.813

Gnomad AMR AF: 0.601

Gnomad ASJ AF: 0.699

Gnomad EAS AF: 0.407

Gnomad SAS AF: 0.735

Gnomad FIN AF: 0.720

Gnomad MID AF: 0.706

Gnomad NFE AF: 0.693

Gnomad OTH AF: 0.654

GnomAD4 exome AF: 0.686 AC: 269517 AN: 392688 Hom.: 93948 Cov.: 2 AF XY: 0.691 AC XY: 142938 AN XY: 206742

African (AFR) AF: 0.632 AC: 7098 AN: 11230

American (AMR) AF: 0.605 AC: 9799 AN: 16198

Ashkenazi Jewish (ASJ) AF: 0.708 AC: 8572 AN: 12104

East Asian (EAS) AF: 0.464 AC: 12450 AN: 26828

South Asian (SAS) AF: 0.767 AC: 32764 AN: 42694

European-Finnish (FIN) AF: 0.714 AC: 17456 AN: 24458

Middle Eastern (MID) AF: 0.772 AC: 1326 AN: 1718

European-Non Finnish (NFE) AF: 0.701 AC: 164570 AN: 234808

Other (OTH) AF: 0.684 AC: 15482 AN: 22650

GnomAD4 genome AF: 0.663 AC: 100762 AN: 152038 Hom.: 33742 Cov.: 32 AF XY: 0.662 AC XY: 49165 AN XY: 74300

African (AFR) AF: 0.638 AC: 26449 AN: 41458

American (AMR) AF: 0.601 AC: 9191 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.699 AC: 2426 AN: 3470

East Asian (EAS) AF: 0.407 AC: 2098 AN: 5158

South Asian (SAS) AF: 0.736 AC: 3545 AN: 4818

European-Finnish (FIN) AF: 0.720 AC: 7632 AN: 10596

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

European-Non Finnish (NFE) AF: 0.693 AC: 47092 AN: 67938

Other (OTH) AF: 0.656 AC: 1385 AN: 2112

Alfa AF: 0.682 Hom.: 40833

Bravo AF: 0.649

TwinsUK AF: 0.691 AC: 2563

ALSPAC AF: 0.691 AC: 2663

Asia WGS AF: 0.640 AC: 2226 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
AlphaMissense	Benign	0.056
BayesDel_addAF	Benign	-0.87	T
BayesDel_noAF	Benign	-0.88
CADD	Benign	5.3
DANN	Benign	0.55
FATHMM_MKL	Benign	0.0030	N
LIST_S2	Benign	0.24	T
MetaRNN	Benign	0.0046	T
PhyloP100		1.1
Sift4G	Benign	1.0	T
Vest4		0.11
MVP		0.63
GERP RS		-0.96
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
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: rs907087; hg19: chr17-37828787;