rs587777709

chr5-68293835-G-Achr5-68293835-G-Cchr5-68293835-G-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1_Moderate PM2 PP3_Strong PP5_Very_Strong

The NM_181523.3(PIK3R1):c.1425+1G>A variant causes a splice donor 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. 2/2 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
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12 O:1
• 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]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PVS1: Splicing variant, 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
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. No scorers claiming Benign.
• 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	UniProt
PIK3R1	NM_181523.3	c.1425+1G>A		splice_donor_variant		ENST00000521381.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PIK3R1	ENST00000521381.6	c.1425+1G>A		splice_donor_variant		1	NM_181523.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3 Other:1

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	-	- -
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	- -

SHORT syndrome Pathogenic:2

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	- -

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	Invitae	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. -

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

- -

PIK3R1-related condition Pathogenic:1

Pathogenic, criteria provided, single submitter

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. -

Immunodeficiency 36 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 15, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.41
Cadd	Pathogenic	34
Dann	Uncertain	1.0
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Pathogenic	1.0	D
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
GERP RS		5.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.99		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs587777709; hg19: chr5-67589663; COSMIC: COSV57123381; COSMIC: COSV57123381;