rs587777389

Positions:

• chr1-9720793-G-A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PM5 PP2 PP3 PP5_Very_Strong

The NM_005026.5(PIK3CD):​c.1573G>A​(p.Glu525Lys) variant causes a missense 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. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E525G) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: PIK3CD NM_005026.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 8.01

Genes affected

PIK3CD (HGNC:8977): (phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta) Phosphoinositide 3-kinases (PI3Ks) phosphorylate inositol lipids and are involved in the immune response. The protein encoded by this gene is a class I PI3K found primarily in leukocytes. Like other class I PI3Ks (p110-alpha p110-beta, and p110-gamma), the encoded protein binds p85 adapter proteins and GTP-bound RAS. However, unlike the other class I PI3Ks, this protein phosphorylates itself, not p85 protein.[provided by RefSeq, Jul 2010]

PIK3CD (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PM1: In a helix (size 8) in uniprot entity PK3CD_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_005026.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-9720794-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 582515.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1}.
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), PIK3CD. . Gene score misZ 4.2747 (greater than the threshold 3.09). Trascript score misZ 6.3833 (greater than threshold 3.09). GenCC has associacion of gene with immunodeficiency 14b, autosomal recessive, immunodeficiency 14, activated PI3K-delta syndrome.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.816
• PP5: Variant 1-9720793-G-A is Pathogenic according to our data. Variant chr1-9720793-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 132807.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-9720793-G-A is described in Lovd as [Likely_pathogenic]. Variant chr1-9720793-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PIK3CD	NM_005026.5	c.1573G>A	p.Glu525Lys	missense_variant	13/24	ENST00000377346.9	NP_005017.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PIK3CD	ENST00000377346.9	c.1573G>A	p.Glu525Lys	missense_variant	13/24	1	NM_005026.5	ENSP00000366563.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 38

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Immunodeficiency 14 Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 525 of the PIK3CD protein (p.Glu525Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with activated PI3K-delta syndrome (PMID: 24165795, 27555459, 27577878, 28104464, 28190860, 29330011). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 132807). 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 expected to disrupt PIK3CD protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects PIK3CD function (PMID: 24165795, 28167755, 29330011). For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The missense variant p.E525K in PIK3CD (NM_005026.5) has been reported in an affected individual (Lucas et al, 2014). It has been submitted to ClinVar as Pathogenic. The p.E525K variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. The p.E525K missense variant is predicted to be damaging by both SIFT and PolyPhen2. The glutamic acid residue at codon 525 of PIK3CD is conserved in all mammalian species. The nucleotide c.1573 in PIK3CD is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Likely Pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2014	- -
Pathogenic, no assertion criteria provided	research	Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine	-	This variant has been identified in an individual with immunodeficiency. Parental mosaicism was noted in an unaffected parent. -

PIK3CD-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 06, 2024

The PIK3CD c.1573G>A variant is predicted to result in the amino acid substitution p.Glu525Lys. This variant has been reported in the heterozygous state in multiple individuals with activated phosphoinositide 3-kinase delta syndrome (see for example, Lucas et al. 2014. PubMed ID: 24165795; Table S1, Stray-Pedersen et al. 2016. PubMed ID: 27577878; Table S3, Similuk et al. 2022. PubMed ID: 35753512). This variant has not been reported in a large population database, indicating this variant is rare. Alternate nucleotide substitutions affecting the same amino acid (p.Glu525Gly and p.Glu525Ala) have been reported in multiple individuals with activated phosphoinositide 3-kinase delta syndrome or primary immunodeficiency (Figure 2, de novo, Marzollo et al. 2021. PubMed ID: 34692603; Figure 1, Tsujita et al. 2016. PubMed ID: 27426521). The c.1573G>A (p.Glu525Lys) variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Uncertain	0.072	D
BayesDel_noAF	Benign	-0.13
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.64	.;D;D;.;D
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	.;D;D;D;.
M_CAP	Pathogenic	0.57	D
MetaRNN	Pathogenic	0.82	D;D;D;D;D
MetaSVM	Benign	-0.36	T
MutationAssessor	Benign	1.9	.;.;L;.;.
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-3.3	D;.;D;.;D
REVEL	Uncertain	0.40
Sift	Uncertain	0.0020	D;.;D;.;D
Sift4G	Uncertain	0.0050	D;D;D;D;D
Polyphen		0.69	P;.;D;P;.
Vest4		0.76
MutPred		0.52		Gain of MoRF binding (P = 0.0106);Gain of MoRF binding (P = 0.0106);.;Gain of MoRF binding (P = 0.0106);Gain of MoRF binding (P = 0.0106);
MVP		0.68
MPC		1.8
ClinPred		0.97	D
GERP RS		5.6
Varity_R		0.89
gMVP		0.65

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs587777389; hg19: chr1-9780851;