rs587777709
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong
The NM_181523.3(PIK3R1):c.1425+1G>A variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: not found (cov: 32)
Consequence
PIK3R1
NM_181523.3 splice_donor, intron
NM_181523.3 splice_donor, intron
Scores
5
1
1
Splicing: ADA: 1.000
2
Clinical Significance
Conservation
PhyloP100: 9.35
Genes affected
PIK3R1 (HGNC:8979): (phosphoinositide-3-kinase regulatory subunit 1) Phosphatidylinositol 3-kinase phosphorylates the inositol ring of phosphatidylinositol at the 3-prime position. The enzyme comprises a 110 kD catalytic subunit and a regulatory subunit of either 85, 55, or 50 kD. This gene encodes the 85 kD regulatory subunit. Phosphatidylinositol 3-kinase plays an important role in the metabolic actions of insulin, and a mutation in this gene has been associated with insulin resistance. Alternative splicing of this gene results in four transcript variants encoding different isoforms. [provided by RefSeq, Jun 2011]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 ACMG points.
PVS1
Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.057471264 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 5-68293835-G-A is Pathogenic according to our data. Variant chr5-68293835-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 372467.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-68293835-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| PIK3R1 | NM_181523.3 | c.1425+1G>A | splice_donor_variant, intron_variant | ENST00000521381.6 | NP_852664.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| PIK3R1 | ENST00000521381.6 | c.1425+1G>A | splice_donor_variant, intron_variant | 1 | NM_181523.3 | ENSP00000428056.1 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Cov.: 27
GnomAD4 exome
Cov.:
27
GnomAD4 genome
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:13Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:3Other:1
| Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Nov 01, 2023 | PIK3R1: PM6:Strong, PM2, PS4:Moderate, PP3, PS3:Supporting - |
| Pathogenic, criteria provided, single submitter | clinical testing | Blueprint Genetics | Oct 19, 2018 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Dec 07, 2016 | The c.1425+1G>A pathogenic variant has been reported previously in association with PASLI disease (Lucas et al., 2014). cDNA studies indicated that c.1425+1G>A results in the skipping of exon 11 (Lucas et al., 2014). This splice site variant destroys the canonical splice donor site in intron 11. It is predicted to cause abnormal gene splicing, either leading to an abnormal message that is subject to nonsense mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. The c.1425+1G>A variant was not observed in approximately 6,400 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Therefore, we interpret this variant to be pathogenic. - |
| not provided, no classification provided | research | MutSpliceDB: a database of splice sites variants effects on splicing, NIH | - | - - |
SHORT syndrome Pathogenic:3
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 21, 2020 | This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center | Jul 27, 2022 | This sequence variant is a single nucleotide substitution (G>A) at the +1 position downstream of the exon 11 canonical splice donor site of the PIK3R1 gene. This is a previously reported variant (ClinVar) which has been observed as a de novo variant in multiple individuals with a combition of phenotypes including short stature, immunodeficiency, hyper IgM syndrome, and hyperactivation of PI3K and AKT (PMID: 28302518, 27076228, 27693481, 25939554, 25488983, 27116393). This variant is not present in approximately 210300 alleles in the gnomAD control population dataset. Splicing studies show that this variant leads to an in-frame deletion of exon 11 (PMID: 25488983, 27076228); the variant protein is constitutively active, due to its ibility to properly interact with p110delta (PMID: 25488983). Based on the available evidence, we consider this variant to be pathogenic. ACMG Criteria: PM1, PM2, PM4, PP3, PP4, PS2, PS3, PS4 - |
SHORT syndrome;C3554689:Agammaglobulinemia 7, autosomal recessive;C4014934:Immunodeficiency 36 Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Mar 29, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 05, 2023 | This sequence change affects a donor splice site in intron 11 of the PIK3R1 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened protein product. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with hypogammaglobulinemia with elevated IgM, activated PI3K-delta syndrome, and SHORT syndrome (PMID: 25488983, 25939554, 27076228, 27116393, 27693481, 28302518). In at least one individual the variant was observed to be de novo. This variant is also known as g.67589663G>A. ClinVar contains an entry for this variant (Variation ID: 372467). Studies have shown that disruption of this splice site results in skipping of exon 11, but is expected to preserve the integrity of the reading-frame (PMID: 27076228). For these reasons, this variant has been classified as Pathogenic. - |
PIK3R1-related disorder Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Jan 11, 2024 | The PIK3R1 c.1425+1G>A variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant has been reported as a recurrent de novo mutation in multiple individuals with activated phosphoinositide 3-kinase δ syndrome type 2 (APDS2) (Lucas et al. 2014. PubMed ID: 25488983; Lougaris et al. 2015. PubMed ID: 25939554; Petrovski et al. 2016. PubMed ID: 27076228; Olbrich et al. 2016. PubMed ID: 27116393; Elkaim et al. 2016. PubMed ID: 27221134; Yazdani et al. 2019. PubMed ID: 30799802). RNA analysis has shown that this variant leads to an in-frame deletion of 42 amino acid residues, and in vitro functional studies using tranformed patient B cells have shown that this deletion leads to reduced p85α protein expression, constitutive activation of the PI3K complex, and upregulation of downstream AKT and mTOR signaling pathways (Petrovski et al. 2016. PubMed ID: 27076228). This variant has not been reported in a large population database, indicating this variant is rare. Several additional variants that disrupt the same splice donor site (c.1425+1G>C/T, +2T>A/G, +2_+3delTG, etc.) have been reported in multiple individuals with ADPS-related phenotypes (Deau et al. 2014. PubMed ID: 25133428; Elkaim et al. 2016. PubMed ID: 27221134). Variants that disrupt the consensus splice donor site in PIK3R1 are expected to be pathogenic. This variant is interpreted as pathogenic. - |
Inborn genetic diseases Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 15, 2017 | - - |
See cases Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Center for Personalized Medicine, Children's Hospital Los Angeles | Dec 21, 2022 | - - |
Inherited Immunodeficiency Diseases Pathogenic:1
| Pathogenic, criteria provided, single submitter | research | NIHR Bioresource Rare Diseases, University of Cambridge | Jan 01, 2019 | - - |
Immunodeficiency 36 Pathogenic:1
| Pathogenic, no assertion criteria provided | literature only | OMIM | Mar 15, 2023 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
GERP RS
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DL_spliceai
Position offset: -1
Find out detailed SpliceAI scores and Pangolin per-transcript scores at