rs869312814

chr17-39673105-T-C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PP3_Strong PP5_Moderate

The NM_033419.5(PGAP3):c.845A>G(p.Asp282Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: PGAP3 NM_033419.5 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 4.82

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]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_033419.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.967
• PP5: Variant 17-39673105-T-C is Pathogenic according to our data. Variant chr17-39673105-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 224644.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-39673105-T-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PGAP3	NM_033419.5	c.845A>G	p.Asp282Gly	missense_variant	7/8	ENST00000300658.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PGAP3	ENST00000300658.9	c.845A>G	p.Asp282Gly	missense_variant	7/8	1	NM_033419.5	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Hyperphosphatasia with intellectual disability syndrome 4 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	Oct 04, 2016	- -
Pathogenic, no assertion criteria provided	research	Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin	Mar 01, 2016	Disease causing variant in homozygous or compound heterozygous state -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
Cadd	Pathogenic	31
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.91	D;.;.
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.95	D;D;D
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.97	D;D;D
MetaSVM	Uncertain	0.39	D
MutationAssessor	Pathogenic	3.7	H;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-6.8	D;D;D
REVEL	Pathogenic	0.76
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.88
MutPred		0.87		Loss of catalytic residue at D282 (P = 0.1272);.;.;
MVP		0.65
MPC		1.2
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.98
gMVP		0.96

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

Publications

LitVar

Other links and lift over

dbSNP: rs869312814; hg19: chr17-37829358;