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GeneBe

2-196842737-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_024989.4(PGAP1):c.2614G>A(p.Val872Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000286 in 1,396,712 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000029 ( 0 hom. )

Consequence

PGAP1
NM_024989.4 missense

Scores

19

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.335
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.074778974).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
PGAP1NM_024989.4 linkuse as main transcriptc.2614G>A p.Val872Ile missense_variant 26/27 ENST00000354764.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
PGAP1ENST00000354764.9 linkuse as main transcriptc.2614G>A p.Val872Ile missense_variant 26/271 NM_024989.4 P1Q75T13-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000434
AC:
1
AN:
230480
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
124836
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:
0.00000938
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000286
AC:
4
AN:
1396712
Hom.:
0
Cov.:
25
AF XY:
0.00000144
AC XY:
1
AN XY:
696086
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000499
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:
9.35e-7
Gnomad4 OTH exome
AF:
0.0000173
GnomAD4 genome
Cov.:
32

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 submitterclinical testingInvitaeAug 31, 2022This variant has not been reported in the literature in individuals affected with PGAP1-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.001%). This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 872 of the PGAP1 protein (p.Val872Ile). 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. 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
0.080
BayesDel_addAF
Benign
-0.27
T
BayesDel_noAF
Benign
-0.63
Cadd
Benign
15
Dann
Benign
0.90
DEOGEN2
Benign
0.070
T
Eigen
Benign
-0.61
Eigen_PC
Benign
-0.47
FATHMM_MKL
Benign
0.28
N
LIST_S2
Benign
0.76
T
M_CAP
Benign
0.0022
T
MetaRNN
Benign
0.075
T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
1.6
L
MutationTaster
Benign
1.0
N
PrimateAI
Benign
0.30
T
PROVEAN
Benign
-0.15
N
REVEL
Benign
0.082
Sift
Benign
0.42
T
Sift4G
Benign
0.19
T
Polyphen
0.0010
B
Vest4
0.15
MutPred
0.42
Gain of glycosylation at S873 (P = 0.1443);
MVP
0.34
MPC
0.16
ClinPred
0.060
T
GERP RS
3.4
Varity_R
0.046
gMVP
0.10

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.060
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.

Other links and lift over

dbSNP: rs1202995401; hg19: chr2-197707461; API