rs199809707

Positions:

chr2-196873710-T-C

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2BP4_ModerateBS1_Supporting

The NM_024989.4(PGAP1):c.1475A>G(p.Asn492Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000135 in 1,612,048 control chromosomes in the GnomAD database, including 1 homozygotes. 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 0.000099 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00014 ( 1 hom. )

Consequence

PGAP1
NM_024989.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.24

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:

PGAP1 (HGNC:):

PGAP1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.09566718).

BS1

Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000139 (203/1459818) while in subpopulation MID AF= 0.00191 (11/5754). AF 95% confidence interval is 0.00107. There are 1 homozygotes in gnomad4_exome. There are 106 alleles in male gnomad4_exome subpopulation. Median coverage is 29. 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	Protein	UniProt
PGAP1	NM_024989.4 linkuse as main transcript	c.1475A>G	p.Asn492Ser	missense_variant	15/27	ENST00000354764.9	NP_079265.2	Q75T13-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PGAP1	ENST00000354764.9 linkuse as main transcript	c.1475A>G	p.Asn492Ser	missense_variant	15/27	1	NM_024989.4	ENSP00000346809.3		Q75T13-1

Frequencies

GnomAD3 genomes

AF:

0.0000986

AC:

AN:

152112

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000239

AC:

AN:

251000

Hom.:

AF XY:

0.000177

AC XY:

AN XY:

135706

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000723

Gnomad ASJ exome

AF:

0.000695

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000327

Gnomad FIN exome

AF:

0.000139

Gnomad NFE exome

AF:

0.000106

Gnomad OTH exome

AF:

0.000491

GnomAD4 exome

AF:

0.000139

AC:

203

AN:

1459818

Hom.:

Cov.:

AF XY:

0.000146

AC XY:

106

AN XY:

726394

show subpopulations

Gnomad4 AFR exome

AF:

0.0000897

Gnomad4 AMR exome

AF:

0.000649

Gnomad4 ASJ exome

AF:

0.000537

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000429

Gnomad4 FIN exome

AF:

0.000150

Gnomad4 NFE exome

AF:

0.0000810

Gnomad4 OTH exome

AF:

0.000182

GnomAD4 genome

AF:

0.0000985

AC:

AN:

152230

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

74414

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000393

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.0000942

Gnomad4 NFE

AF:

0.0000442

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000113

Hom.:

Bravo

AF:

0.000128

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000117

AC:

ExAC

AF:

0.000157

AC:

Asia WGS

AF:

0.000290

AC:

AN:

3466

EpiCase

AF:

0.000164

EpiControl

AF:

0.000296

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Intellectual disability, autosomal recessive 42

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 17, 2022

This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 492 of the PGAP1 protein (p.Asn492Ser). This variant is present in population databases (rs199809707, gnomAD 0.08%). 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: 541839). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.078

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.51

CADD

Benign

DANN

Benign

0.93

DEOGEN2

Benign

0.11

T;.

Eigen

Benign

-0.31

Eigen_PC

Benign

-0.11

FATHMM_MKL

Uncertain

0.77

LIST_S2

Benign

0.77

T;T

M_CAP

Benign

0.0051

MetaRNN

Benign

0.096

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.46

N;N

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-1.1

N;N

REVEL

Benign

0.077

Sift

Benign

0.39

T;T

Sift4G

Benign

0.57

T;T

Polyphen

0.20

B;B

Vest4

0.21

MVP

0.55

MPC

0.16

ClinPred

0.013

GERP RS

3.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.063

gMVP

0.37

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