5-68295271-C-G

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PS1 PM1 PM2 PM5 PP2 PP3 PP5_Moderate

The NM_181523.3(PIK3R1):c.1692C>G(p.Asn564Lys) variant causes a missense change involving the alteration of a non-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 Pathogenic (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N564D) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PIK3R1 NM_181523.3 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 2.80

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 14 ACMG points.

• PS1: Transcript NM_181523.3 (PIK3R1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 376066
• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_181523.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr5-68295269-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 376261.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant where missense usually causes diseases, PIK3R1
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.758
• PP5: Variant 5-68295271-C-G is Pathogenic according to our data. Variant chr5-68295271-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 376067.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PIK3R1	NM_181523.3	c.1692C>G	p.Asn564Lys	missense_variant	13/16	ENST00000521381.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PIK3R1	ENST00000521381.6	c.1692C>G	p.Asn564Lys	missense_variant	13/16	1	NM_181523.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Neoplasm Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

Jul 14, 2015

- -

SHORT syndrome;C3554689:Agammaglobulinemia 7, autosomal recessive;C4014934:Immunodeficiency 36 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

May 03, 2023

For these reasons, this variant has been classified as Pathogenic. 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 PIK3R1 protein function. ClinVar contains an entry for this variant (Variation ID: 376067). This missense change has been observed in individual(s) with activated PI3K delta syndrome and/or clinical features of activated PI3K delta syndrome (PMID: 28104464, 29051493; Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 564 of the PIK3R1 protein (p.Asn564Lys). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Benign	-0.073	T
BayesDel_noAF	Benign	-0.34
Cadd	Benign	23
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.87	D;D;.;.;.
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Benign	0.037	D
MetaRNN	Pathogenic	0.76	D;D;D;D;D
MetaSVM	Benign	-0.80	T
MutationAssessor	Uncertain	2.5	M;M;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-4.0	D;D;D;D;D
REVEL	Benign	0.18
Sift	Uncertain	0.0060	D;D;D;D;D
Sift4G	Uncertain	0.013	D;D;D;D;D
Polyphen		1.0	D;D;D;D;.
Vest4		0.79
MutPred		0.35		Loss of ubiquitination at K561 (P = 0.0256);Loss of ubiquitination at K561 (P = 0.0256);.;.;.;
MVP		0.70
MPC		2.5
ClinPred		0.99	D
GERP RS		2.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.86
gMVP		0.78

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: rs773686816; hg19: chr5-67591099; COSMIC: COSV57123079; COSMIC: COSV57123079;