17-39673094-T-C

Position:

chr17-39673094-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate

The NM_033419.5(PGAP3):c.856A>G(p.Ile286Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000273 in 1,609,388 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000027 ( 0 hom. )

Consequence

PGAP3
NM_033419.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 0.779

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:

PGAP3 (HGNC:):

PGAP3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM1

In a transmembrane_region Helical (size 19) in uniprot entity PGAP3_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) in NM_033419.5

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.2571779).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PGAP3	NM_033419.5 linkuse as main transcript	c.856A>G	p.Ile286Val	missense_variant	7/8	ENST00000300658.9	NP_219487.3	Q96FM1-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PGAP3	ENST00000300658.9 linkuse as main transcript	c.856A>G	p.Ile286Val	missense_variant	7/8	1	NM_033419.5	ENSP00000300658.4		Q96FM1-1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152112

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000124

AC:

AN:

241286

Hom.:

AF XY:

0.0000154

AC XY:

AN XY:

130082

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000274

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000274

AC:

AN:

1457276

Hom.:

Cov.:

AF XY:

0.0000373

AC XY:

AN XY:

724390

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:

0.0000333

Gnomad4 OTH exome

AF:

0.0000498

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152112

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74306

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000282

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hyperphosphatasia with intellectual disability syndrome 4

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

May 25, 2020

A heterozygous missense variant was identified, NM_033419.4(PGAP3):c.856A>G in exon 7 of the PGAP3 gene (NB: this variant is non-coding in alternative transcripts). This substitution is predicted to create a minor amino acid change from an isoleucine to a valine at position 286 of the protein; NP_219487.3(PGAP3):p.(Ile286Val). The isoleucine at this position has low conservation (100 vertebrates, UCSC), and is located within the Per1-like family domain (NCBI, PDB). In silico software predicts this variant to be tolerated (PolyPhen2, PROVEAN, MutationAssessor). The variant is present in the gnomAD population database at a frequency of 0.0012% (3 heterozygotes, 0 homozygotes). This variant has not previously been reported in clinical cases. Analysis of parental samples indicated that this variant is paternally inherited. Based on information available at the time of curation, this variant has been classified as a VUS with LOW CLINICAL RELEVANCE. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jan 09, 2022

Has not been previously published as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.080

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.54

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.35

T;.;.

Eigen

Benign

-0.15

Eigen_PC

Benign

0.016

FATHMM_MKL

Uncertain

0.76

LIST_S2

Benign

0.80

T;T;T

M_CAP

Benign

0.0024

MetaRNN

Benign

0.26

T;T;T

MetaSVM

Benign

-0.92

MutationAssessor

Benign

0.83

L;.;.

MutationTaster

Benign

0.98

D;D;D;D

PrimateAI

Benign

0.42

PROVEAN

Benign

-0.85

N;N;N

REVEL

Benign

0.054

Sift

Benign

0.21

T;T;T

Sift4G

Benign

0.16

T;T;T

Polyphen

0.15

B;B;.

Vest4

0.23

MutPred

0.61

Gain of glycosylation at S290 (P = 0.1953);.;.;

MVP

0.63

MPC

0.29

ClinPred

0.30

GERP RS

4.3

Varity_R

0.11

gMVP

0.42

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over