17-39673099-T-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_033419.5(PGAP3):c.851A>G(p.His284Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,457,284 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H284Y) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PGAP3 NM_033419.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 5.86

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 18 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, 2 uncertain in NM_033419.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-39673100-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 800935.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.976
• PP5: Variant 17-39673099-T-C is Pathogenic according to our data. Variant chr17-39673099-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 599004.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-39673099-T-C is described in Lovd as [Likely_pathogenic]. Variant chr17-39673099-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PGAP3	NM_033419.5	c.851A>G	p.His284Arg	missense_variant	7/8	ENST00000300658.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PGAP3	ENST00000300658.9	c.851A>G	p.His284Arg	missense_variant	7/8	1	NM_033419.5	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1457284 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 724414

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hyperphosphatasia with intellectual disability syndrome 4 Pathogenic:3

Likely pathogenic, criteria provided, single submitter	research	Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 29, 2024	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 07, 2022	- -

Seizure;C0235833:Congenital diaphragmatic hernia;C0239234:Low-set ears;C0557874:Global developmental delay;C1837397:Severe global developmental delay;C1849950:Agenesis of maxillary lateral incisor;C1855728:Low posterior hairline;C2981150:Cleft palate;C3553450:Profound global developmental delay;C3806604:Infantile axial hypotonia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Center for Personalized Medicine, Children's Hospital Los Angeles

-

- -

See cases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Center for Personalized Medicine, Children's Hospital Los Angeles

Dec 21, 2022

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Apr 06, 2020

Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30755392, 30919572, 30345601, 26077850, 28794914) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
Cadd	Pathogenic	27
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.88	D;.;.
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.92	D;D;D
M_CAP	Uncertain	0.087	D
MetaRNN	Pathogenic	0.98	D;D;D
MetaSVM	Uncertain	0.12	D
MutationAssessor	Pathogenic	3.7	H;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.79	T
PROVEAN	Pathogenic	-7.8	D;D;D
REVEL	Uncertain	0.48
Sift	Pathogenic	0.0	D;D;D
Sift4G	Uncertain	0.0090	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.96
MutPred		0.91		Gain of catalytic residue at H284 (P = 0.1306);.;.;
MVP		0.75
MPC		1.2
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.93
gMVP		0.98

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: rs776720232; hg19: chr17-37829352; COSMIC: COSV54092929; COSMIC: COSV54092929;