17-39684715-G-T

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PM2PM5PP3_StrongPP5_Moderate

The NM_033419.5(PGAP3):c.314C>A(p.Pro105Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,666 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. P105R) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

PGAP3
NM_033419.5 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 8.66

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PM1

In a transmembrane_region Helical (size 20) in uniprot entity PGAP3_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) 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 chr17-39684715-G-C is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.964

PP5

Variant 17-39684715-G-T is Pathogenic according to our data. Variant chr17-39684715-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1705418.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-39684715-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PGAP3	NM_033419.5 link	c.314C>A	p.Pro105Gln	missense_variant	Exon 3 of 8	ENST00000300658.9	NP_219487.3	Q96FM1-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PGAP3	ENST00000300658.9 link	c.314C>A	p.Pro105Gln	missense_variant	Exon 3 of 8	1	NM_033419.5	ENSP00000300658.4		Q96FM1-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1459666

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726038

show subpopulations

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:

9.00e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Hyperphosphatasia with intellectual disability syndrome 4

Pathogenic:1

Sep 01, 2022

3billion

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is not observed in the gnomAD v2.1.1 dataset. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.68; 3Cnet: 0.92). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (PMID: 29531774). A different missense change at the same codon (p.Pro105Arg) has been reported to be associated with PGAP3-related disorder (ClinVar ID: VCV000125440 / PMID: 24439110 ).Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.50

BayesDel_noAF

Pathogenic

0.48

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.87

D;D;.;.

Eigen

Pathogenic

0.80

Eigen_PC

Pathogenic

0.67

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.93

D;D;D;D

M_CAP

Uncertain

0.20

MetaRNN

Pathogenic

0.96

D;D;D;D

MetaSVM

Uncertain

0.34

MutationAssessor

Pathogenic

3.5

.;H;H;.

PrimateAI

Uncertain

0.59

PROVEAN

Pathogenic

-7.3

.;D;D;.

REVEL

Pathogenic

0.68

Sift

Pathogenic

0.0

.;D;D;.

Sift4G

Pathogenic

0.0

D;D;D;.

Polyphen

1.0

.;D;.;.

Vest4

0.90

MutPred

0.83

Gain of catalytic residue at P105 (P = 0.0107);Gain of catalytic residue at P105 (P = 0.0107);Gain of catalytic residue at P105 (P = 0.0107);.;

MVP

0.62

MPC

1.0

ClinPred

1.0

GERP RS

4.5

Varity_R

0.95

gMVP

0.85

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over