chr5-68295269-A-G

Variant names:

• chr5-68295269-A-G
• rs1057519841
• NM_181523.3:c.1690A>G

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1 PM2 PM5 PP5_Moderate

The NM_181523.3(PIK3R1):​c.1690A>G​(p.Asn564Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N564K) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PIK3R1 NM_181523.3 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 9.32
• Publications: 81 publications found

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]

PIK3R1 Gene-Disease associations (from GenCC):

• immunodeficiency 36 with lymphoproliferation

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen
• SHORT syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet
• agammaglobulinemia 7, autosomal recessive

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• activated PI3K-delta syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• autosomal agammaglobulinemia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PM1: In a hotspot region, there are 2 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 chr5-68295271-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 376067.
• PP5: Variant 5-68295269-A-G is Pathogenic according to our data. Variant chr5-68295269-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 376261.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIK3R1	NM_181523.3	c.1690A>G	p.Asn564Asp	missense_variant	Exon 13 of 16	ENST00000521381.6	NP_852664.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PIK3R1	ENST00000521381.6	c.1690A>G	p.Asn564Asp	missense_variant	Exon 13 of 16	1	NM_181523.3	ENSP00000428056.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1461840 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727214

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39680

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111986

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Vascular malformation Pathogenic:1

Sep 21, 2023

Clinical Genomics Laboratory, Washington University in St. Louis

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The PIK3R1 c.1690A>G (p.Asn564Asp) variant was identified at an allelic fraction consistent with somatic origin. It has been identified in numerous individuals with vascular anomalies and overgrowth (Cottrell et al., PMID: 34040190). This variant has been reported as a pathogenic somatic variant by a single submitter (ClinVar ID: 376261). It also has been reported in 55 cases in the cancer database (COSMIC ID: COSV57124003). PIK3R1 c.1690A>G (p.Asn564Asp) is absent from the general population (gnomAD v.3.1.2), indicating it is not a common variant. This variant resides within the helical domain, amino acids 525-696, of phosphatidylinositol 3-Kinase (PI3K) protein complex that is defined as a critical functional domain (Huang CH et al., PMID: 18079394). The PIK3R1 is a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (Cottrell et al., PMID: 34040190). Functional patient-derived cells studies show that this asparagine substitution at codon 564 leads to autonomous phosphorylation of AKT and activation of the downstream AKT-mTOR signaling, indicating that this variant impacts protein function (Jaiswal BS et al., PMID: 19962665; Urick ME et al., PMID: 21478295). Based on an internally-developed protocol informed by the ACMG/AMP guidelines (Richards S et al., PMID: 25741868) and gene-specific practices from the ClinGen Criteria Specification Registry, the PIK3R1 c.1690A>G (p.Asn564Asp) variant is classified as pathogenic. -

Vascular Malformations and Overgrowth Pathogenic:1

Nov 08, 2020

Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

This alteration is both well-represented in cancer as identified in the COSMIC database with >=20 documented instances and also considered to occur in a statistically significant hotspot or region according to cancerhotspots.org database [PS_CANCER], is of apparent somatic mosaic etiology with strong supporting evidence including no discernible strand bias, in a region absent of repetition and sequence homology, with clean, high-quality reads, having a variant allele fraction >= 3% [PS2], is supported by well-established models demonstrating downstream impact of the variant on RNA structure, gene expression, or protein function [PS3], is at increased prevalence in our cohort, with >= 5 occurrences in unrelated individuals [PS4_Mod], and is a missense variant in a gene that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease [PP2]. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Benign	-0.022	T
BayesDel_noAF	Benign	-0.27
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.81	D;D;.;.;.
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	.;D;D;D;D
M_CAP	Benign	0.042	D
MetaRNN	Uncertain	0.59	D;D;D;D;D
MetaSVM	Benign	-0.70	T
MutationAssessor	Uncertain	2.2	M;M;.;.;.
PhyloP100		9.3
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-3.4	D;D;D;D;D
REVEL	Uncertain	0.36
Sift	Uncertain	0.0050	D;D;D;D;D
Sift4G	Uncertain	0.016	D;D;D;D;D
Polyphen		0.93	P;P;B;B;.
Vest4		0.68
MutPred		0.28		Loss of MoRF binding (P = 0.0393);Loss of MoRF binding (P = 0.0393);.;.;.;
MVP		0.58
MPC		2.4
ClinPred		0.99	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.90
gMVP		0.76
Mutation Taster		=2/98	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1057519841; hg19: chr5-67591097; COSMIC: COSV57124003; COSMIC: COSV57124003;