4-521842-G-A
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PVS1PP5
The NM_001127178.3(PIGG):c.1515G>A(p.Trp505Ter) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00106 in 1,614,208 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_001127178.3 stop_gained
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 |
---|---|---|---|---|---|---|---|
PIGG | NM_001127178.3 | c.1515G>A | p.Trp505Ter | stop_gained | 8/13 | ENST00000453061.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PIGG | ENST00000453061.7 | c.1515G>A | p.Trp505Ter | stop_gained | 8/13 | 1 | NM_001127178.3 | P4 |
Frequencies
GnomAD3 genomes AF: 0.000703 AC: 107AN: 152204Hom.: 1 Cov.: 33
GnomAD3 exomes AF: 0.000660 AC: 166AN: 251480Hom.: 0 AF XY: 0.000633 AC XY: 86AN XY: 135914
GnomAD4 exome AF: 0.00110 AC: 1612AN: 1461886Hom.: 1 Cov.: 32 AF XY: 0.00106 AC XY: 772AN XY: 727242
GnomAD4 genome AF: 0.000702 AC: 107AN: 152322Hom.: 1 Cov.: 33 AF XY: 0.000752 AC XY: 56AN XY: 74480
ClinVar
Submissions by phenotype
not provided Pathogenic:8
Likely pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Pathogenic, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Likely pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Feb 08, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Sep 13, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 10, 2022 | Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 31414351, 31980526, 34113002, 26996948, 34535746, 33921431) - |
Pathogenic, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Mar 01, 2024 | PIGG: PVS1, PM3, PM2:Supporting - |
Intellectual disability, autosomal recessive 53 Pathogenic:5
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jun 18, 2020 | This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 10, 2024 | This sequence change creates a premature translational stop signal (p.Trp505*) in the PIGG gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PIGG are known to be pathogenic (PMID: 26996948, 28581210, 28771251). This variant is present in population databases (rs150259543, 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 PIGG-related conditions. ClinVar contains an entry for this variant (Variation ID: 476318). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Feb 02, 2022 | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with autosomal recessive intellectual disability 53 (MIM#616917). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0253 - This variant is hemizygous. This individual has a terminal 4p16.3 deletion encompassing the PIGG gene on the other allele. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (186 heterozygotes, 0 homozygotes), however there is 1 homozygote present in gnomAD v3. (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. Many other variants predicted to result in a loss of function have previously been reported in individuals with autosomal recessive intellectual disability 53 (MIM#616917) (ClinVar, DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. The variant has previously been reported as pathogenic in at least five individuals with autosomal recessive intellectual disability 53 (MIM#616917) (ClinVar). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 21, 2023 | Variant summary: PIGG c.1515G>A (p.Trp505X) results in a premature termination codon, predicted to cause absence of the protein due to nonsense mediated decay, which is a commonly known mechanism for disease. The variant allele was found at a frequency of 0.00066 in 251480 control chromosomes, predominantly at a frequency of 0.0012 within the Non-Finnish European subpopulation in the gnomAD database. c.1515G>A has been reported in the literature in at least one homozygous individual affected with Autism Spectrum Disorder-Asperger type (Arteche-Lopez_2021). The variant was also found in another homozygous individual with seizures and mild clumsiness, although this second individual was too young to evaluate for intellectual disability (Trembley-Laganiere_2021). Ten submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, and classified it as pathogenic (n=7), likely pathogenic (n=2), or likely benign (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center | Oct 03, 2022 | PVS1, PM3 - |
Intellectual disability, autosomal recessive 53;C5676953:BLOOD GROUP, EMM SYSTEM Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Sep 20, 2021 | - - |
Inborn genetic diseases Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 30, 2021 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at