rs201572812
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP3_ModerateBS2
The NM_003978.5(PSTPIP1):c.1208G>A(p.Gly403Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000466 in 1,612,012 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G403R) has been classified as Likely benign.
Frequency
Consequence
NM_003978.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PSTPIP1 | NM_003978.5 | c.1208G>A | p.Gly403Glu | missense_variant | 15/15 | ENST00000558012.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PSTPIP1 | ENST00000558012.6 | c.1208G>A | p.Gly403Glu | missense_variant | 15/15 | 1 | NM_003978.5 | P3 |
Frequencies
GnomAD3 genomes ? AF: 0.000269 AC: 41AN: 152152Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000211 AC: 52AN: 246996Hom.: 0 AF XY: 0.000275 AC XY: 37AN XY: 134638
GnomAD4 exome AF: 0.000487 AC: 711AN: 1459860Hom.: 3 Cov.: 31 AF XY: 0.000464 AC XY: 337AN XY: 726178
GnomAD4 genome ? AF: 0.000269 AC: 41AN: 152152Hom.: 0 Cov.: 32 AF XY: 0.000229 AC XY: 17AN XY: 74328
ClinVar
Submissions by phenotype
Pyogenic arthritis-pyoderma gangrenosum-acne syndrome Uncertain:2Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Oct 26, 2023 | The PSTPIP1 c.1208G>A; p.Gly403Glu variant (rs201572812), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 242306). This variant is found in the non-Finnish European population with an overall allele frequency of 0.04% (52/126858 alleles) in the Genome Aggregation Database. The glycine at codon 403 is moderately conserved and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Additionally, another amino acid substitution at this codon (p.Gly403Arg) has been reported in an individual with pyoderma gangrenosum, acne and ulcerative colitis, although its clinical significance in this individual was not demonstrated (Zeeli 2015). Due to limited information, the clinical significance of the p.Gly403Glu variant is uncertain at this time. References: Zeeli T et al. Pyoderma gangrenosum, acne and ulcerative colitis in a patient with a novel mutation in the PSTPIP1 gene. Clin Exp Dermatol. 2015 Jun;40(4):367-72. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 19, 2024 | This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 403 of the PSTPIP1 protein (p.Gly403Glu). This variant is present in population databases (rs201572812, gnomAD 0.04%), 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 PSTPIP1-related conditions. ClinVar contains an entry for this variant (Variation ID: 242306). 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) performed at Invitae indicates that this missense variant is not expected to disrupt PSTPIP1 protein function with a negative predictive value of 80%. 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. - |
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jan 28, 2016 | The G403E variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The variant was not observed at any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. G403E is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position within the SH3 region that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. A missense variant in the same codon (G403R) has been reported in the Human Gene Mutation Database in association with pyoderma gangrenosum, acne, and ulcerative colitis (Stenson et al., 2014), supporting the functional importance of this region of the protein. However, the pathogenicity of missense changes in the SH3 region of the PSTPIP1 protein is unclear, as pathogenic variants associated with PAPA syndrome have traditionally been identified in the coiled-coil domain region. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Jul 08, 2021 | - - |
Autoinflammatory syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Feb 01, 2020 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at