rs142320636

chr2-196916564-T-Cchr2-196916564-T-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4BS1_Supporting

The NM_024989.4(PGAP1):c.331A>G(p.Lys111Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00128 in 1,612,328 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00075 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0013 ( 1 hom. )

Consequence

PGAP1
NM_024989.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:9

Conservation

PhyloP100: 7.60

Variant links:

Genes affected

PGAP1 (HGNC:25712): (post-GPI attachment to proteins inositol deacylase 1) The protein encoded by this gene functions early in the glycosylphosphatidylinositol (GPI) biosynthetic pathway, catalyzing the inositol deacylation of GPI. The encoded protein is required for the production of GPI that can attach to proteins, and this may be an important factor in the transport of GPI-anchored proteins from the endoplasmic reticulum to the Golgi. Defects in this gene are a cause an autosomal recessive form of cognitive impairment. [provided by RefSeq, Jul 2017]

PGAP1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.34524554).

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000748 (114/152336) while in subpopulation AMR AF= 0.00124 (19/15302). AF 95% confidence interval is 0.00102. There are 1 homozygotes in gnomad4. There are 48 alleles in male gnomad4 subpopulation. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PGAP1	NM_024989.4 linkuse as main transcript	c.331A>G	p.Lys111Glu	missense_variant	3/27	ENST00000354764.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PGAP1	ENST00000354764.9 linkuse as main transcript	c.331A>G	p.Lys111Glu	missense_variant	3/27	1	NM_024989.4	P1	Q75T13-1

Frequencies

GnomAD3 genomes

AF:

0.000749

AC:

114

AN:

152218

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00124

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00318

Gnomad NFE

AF:

0.00123

Gnomad OTH

AF:

0.00239

GnomAD3 exomes

AF:

0.000844

AC:

210

AN:

248718

Hom.:

AF XY:

0.000900

AC XY:

121

AN XY:

134482

show subpopulations

Gnomad AFR exome

AF:

0.000309

Gnomad AMR exome

AF:

0.00133

Gnomad ASJ exome

AF:

0.000100

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000133

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00133

Gnomad OTH exome

AF:

0.000828

GnomAD4 exome

AF:

0.00133

AC:

1949

AN:

1459992

Hom.:

Cov.:

AF XY:

0.00124

AC XY:

899

AN XY:

726262

show subpopulations

Gnomad4 AFR exome

AF:

0.000359

Gnomad4 AMR exome

AF:

0.00144

Gnomad4 ASJ exome

AF:

0.0000384

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000105

Gnomad4 FIN exome

AF:

0.0000375

Gnomad4 NFE exome

AF:

0.00161

Gnomad4 OTH exome

AF:

0.00111

GnomAD4 genome

AF:

0.000748

AC:

114

AN:

152336

Hom.:

Cov.:

AF XY:

0.000644

AC XY:

AN XY:

74488

show subpopulations

Gnomad4 AFR

AF:

0.0000962

Gnomad4 AMR

AF:

0.00124

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000941

Gnomad4 NFE

AF:

0.00123

Gnomad4 OTH

AF:

0.00237

Alfa

AF:

0.00103

Hom.:

Bravo

AF:

0.000937

TwinsUK

AF:

0.00189

AC:

ALSPAC

AF:

0.00156

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00151

AC:

ExAC

AF:

0.000692

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Intellectual disability, autosomal recessive 42

Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Mar 02, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Knight Diagnostic Laboratories, Oregon Health and Sciences University	Nov 18, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Sep 23, 2022	This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 111 of the PGAP1 protein (p.Lys111Glu). This variant is present in population databases (rs142320636, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with PGAP1-related conditions. ClinVar contains an entry for this variant (Variation ID: 436297). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PGAP1 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Jan 15, 2019	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

not provided

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2016	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jun 08, 2016

- -

Hereditary spastic paraplegia

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Nov 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.96

BayesDel_addAF

Uncertain

0.090

BayesDel_noAF

Pathogenic

0.35

Cadd

Uncertain

Dann

Uncertain

1.0

DEOGEN2

Uncertain

0.52

D;.;T

Eigen

Uncertain

0.62

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.88

D;D;D

M_CAP

Uncertain

0.19

MetaRNN

Benign

0.35

T;T;T

MetaSVM

Uncertain

0.37

MutationAssessor

Benign

1.6

L;L;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.77

PROVEAN

Uncertain

-3.6

D;D;D

REVEL

Pathogenic

0.80

Sift

Pathogenic

0.0

D;D;D

Sift4G

Uncertain

0.019

D;D;T

Polyphen

1.0

D;P;.

Vest4

0.87

MVP

0.90

MPC

0.91

ClinPred

0.050

GERP RS

5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.91

gMVP

0.87

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