rs879255233
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PP3_Strong
The NM_014489.4(PGAP2):āc.563T>Cā(p.Leu188Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,461,874 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 Uncertain significance (ā ).
Frequency
Genomes: not found (cov: 31)
Exomes š: 0.0000027 ( 0 hom. )
Consequence
PGAP2
NM_014489.4 missense
NM_014489.4 missense
Scores
9
7
1
Clinical Significance
Conservation
PhyloP100: 7.16
Genes affected
PGAP2 (HGNC:17893): (post-GPI attachment to proteins 2) The protein encoded by this gene plays a role in the maturation of glycosylphosphatidylinositol (GPI) anchors on GPI-anchored proteins. Mutations in this gene are associated with an autosomal recessive syndrome characterized by hyperphosphatasia and intellectual disability. [provided by RefSeq, Jul 2017]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
PM1
?
In a chain Post-GPI attachment to proteins factor 2 (size 253) in uniprot entity PGAP2_HUMAN there are 26 pathogenic changes around while only 5 benign (84%) in NM_014489.4
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.97
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PGAP2 | NM_014489.4 | c.563T>C | p.Leu188Ser | missense_variant | 4/7 | ENST00000278243.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PGAP2 | ENST00000278243.9 | c.563T>C | p.Leu188Ser | missense_variant | 4/7 | 1 | NM_014489.4 | A1 |
Frequencies
GnomAD3 genomes ? Cov.: 31
GnomAD3 genomes
?
Cov.:
31
GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461874Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2AN XY: 727238
GnomAD4 exome
AF:
AC:
4
AN:
1461874
Hom.:
Cov.:
33
AF XY:
AC XY:
2
AN XY:
727238
Gnomad4 AFR exome
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GnomAD4 genome ? Cov.: 31
GnomAD4 genome
?
Cov.:
31
ClinVar
Significance: Uncertain significance
Submissions summary: Pathogenic:1Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Hyperphosphatasia with intellectual disability syndrome 3 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Apr 04, 2013 | - - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 08, 2021 | The c.563T>C (p.L188S) alteration is located in exon 4 (coding exon 3) of the PGAP2 gene. This alteration results from a T to C substitution at nucleotide position 563, causing the leucine (L) at amino acid position 188 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D;D;.;D;D;D;D;D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D;D;D;D
MetaSVM
Uncertain
T
MutationTaster
Benign
D;D;D;D;D;D;D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D;.;.;.;D;.;D;D;D
REVEL
Uncertain
Sift
Pathogenic
D;D;.;.;.;D;.;D;D;D
Sift4G
Pathogenic
D;D;D;D;D;D;D;D;D;D
Polyphen
D;.;.;.;.;.;.;.;.;.
Vest4
MutPred
Loss of stability (P = 0.0176);Loss of stability (P = 0.0176);.;.;.;.;.;.;.;.;
MVP
MPC
1.4
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at