rs1057519841

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PP2PP5_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 (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

PIK3R1
NM_181523.3 missense

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 9.32

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PM1

In a helix (size 68) in uniprot entity P85A_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_181523.3

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in the PIK3R1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 14 curated pathogenic missense variants (we use a threshold of 10). The gene has 11 curated benign missense variants. Gene score misZ: 2.7206 (below the threshold of 3.09). Trascript score misZ: 3.4358 (above the threshold of 3.09). GenCC associations: The gene is linked to agammaglobulinemia 7, autosomal recessive, autosomal agammaglobulinemia, immunodeficiency 36, SHORT syndrome, activated PI3K-delta syndrome.

PP5

Variant 5-68295269-A-G is Pathogenic according to our data. 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. Variant chr5-68295269-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIK3R1	NM_181523.3 link	c.1690A>G	p.Asn564Asp	missense_variant	Exon 13 of 16	ENST00000521381.6	NP_852664.1	P27986-1A0A2X0SFG1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PIK3R1	ENST00000521381.6 link	c.1690A>G	p.Asn564Asp	missense_variant	Exon 13 of 16	1	NM_181523.3	ENSP00000428056.1		P27986-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1461840

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727214

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

LINK: link

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

BayesDel_noAF

Benign

-0.27

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.81

D;D;.;.;.

Eigen

Uncertain

0.42

Eigen_PC

Uncertain

0.47

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.94

.;D;D;D;D

M_CAP

Benign

0.042

MetaRNN

Uncertain

0.59

D;D;D;D;D

MetaSVM

Benign

-0.70

MutationAssessor

Uncertain

2.2

M;M;.;.;.

PrimateAI

Pathogenic

0.88

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

GERP RS

4.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.90

gMVP

0.76

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over