chr17-39673123-G-A
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PP3_StrongPP5
The NM_033419.5(PGAP3):c.827C>T(p.Pro276Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000523 in 1,607,474 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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P276P) has been classified as Likely benign.
Frequency
Consequence
NM_033419.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PGAP3 | NM_033419.5 | c.827C>T | p.Pro276Leu | missense_variant | 7/8 | ENST00000300658.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PGAP3 | ENST00000300658.9 | c.827C>T | p.Pro276Leu | missense_variant | 7/8 | 1 | NM_033419.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000592 AC: 9AN: 152152Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000508 AC: 12AN: 236368Hom.: 0 AF XY: 0.0000550 AC XY: 7AN XY: 127238
GnomAD4 exome AF: 0.0000515 AC: 75AN: 1455322Hom.: 0 Cov.: 34 AF XY: 0.0000567 AC XY: 41AN XY: 723166
GnomAD4 genome ? AF: 0.0000592 AC: 9AN: 152152Hom.: 0 Cov.: 33 AF XY: 0.0000538 AC XY: 4AN XY: 74320
ClinVar
Submissions by phenotype
Hyperphosphatasia with intellectual disability syndrome 4 Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 08, 2022 | Variant summary: PERLD1 c.827C>T (p.Pro276Leu) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6.6e-05 in 381074 control chromosomes. This frequency does not allow conclusions about variant significance to be made. c.827C>T has been reported in the literature in multiple homozygous individuals affected with PERLD1/PGAP3-associated disorders (e.g. Mitani_2021, Levchenko_2022). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, with two laboratories classifying the variant as uncertain significance and one lab classifying the variant as likely pathogenic. However, literature identifying the c.827C>T homozygous individuals with PERLD1/PGAP3-associated disorders (Mitani_2021 and Levchenko_2022) was published after these ClinVar submissions. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jun 24, 2022 | - - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 23, 2024 | This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 276 of the PGAP3 protein (p.Pro276Leu). This variant is present in population databases (rs750093817, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of PGAP3-related conditions (Invitae; GeneDx). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 426134). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PGAP3 protein function. For these reasons, this variant has been classified as Pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Nov 09, 2020 | Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 26077850, 24439110, 17314402, 28390064, 22265715) - |
PGAP3-related disorder Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Feb 06, 2023 | The PGAP3 c.827C>T variant is predicted to result in the amino acid substitution p.Pro276Leu. This variant has been found in the homozygous state in three individuals from two cohorts of patients with neurodevelopmental and/or intellectual disorders (Table S2 in Mitani et al. 2021. PubMed ID: 34582790; Levchenko et al. 2022. PubMed ID: 35887114). This variant is reported in 0.013% of alleles in individuals of European (Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/17-37829376-G-A). This variant is interpreted as likely pathogenic. - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 22, 2015 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at