rs3730089

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBA1

The NM_181523.3(PIK3R1):c.978G>A(p.Met326Ile) variant causes a missense change. The variant allele was found at a frequency of 0.171 in 1,610,794 control chromosomes in the GnomAD database, including 26,801 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.22 ( 4645 hom., cov: 32)

Exomes 𝑓: 0.17 ( 22156 hom. )

Consequence

PIK3R1
NM_181523.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7O:1

Conservation

PhyloP100: 4.65

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 Benign. Variant got -19 ACMG points.

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.

BP4

Computational evidence support a benign effect (MetaRNN=0.0020537376).

BP6

Variant 5-68292320-G-A is Benign according to our data. Variant chr5-68292320-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 135039.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-68292320-G-A is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.375 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIK3R1	NM_181523.3 link	c.978G>A	p.Met326Ile	missense_variant	Exon 8 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.978G>A	p.Met326Ile	missense_variant	Exon 8 of 16	1	NM_181523.3	ENSP00000428056.1		P27986-1

Frequencies

GnomAD3 genomes

AF:

0.219

AC:

33242

AN:

151966

Hom.:

4637

Cov.:

show subpopulations

Gnomad AFR

AF:

0.380

Gnomad AMI

AF:

0.141

Gnomad AMR

AF:

0.224

Gnomad ASJ

AF:

0.170

Gnomad EAS

AF:

0.173

Gnomad SAS

AF:

0.0759

Gnomad FIN

AF:

0.126

Gnomad MID

AF:

0.152

Gnomad NFE

AF:

0.152

Gnomad OTH

AF:

0.187

GnomAD3 exomes

AF:

0.178

AC:

44681

AN:

251082

Hom.:

4846

AF XY:

0.166

AC XY:

22545

AN XY:

135740

show subpopulations

Gnomad AFR exome

AF:

0.384

Gnomad AMR exome

AF:

0.286

Gnomad ASJ exome

AF:

0.170

Gnomad EAS exome

AF:

0.175

Gnomad SAS exome

AF:

0.0780

Gnomad FIN exome

AF:

0.129

Gnomad NFE exome

AF:

0.155

Gnomad OTH exome

AF:

0.150

GnomAD4 exome

AF:

0.166

AC:

242830

AN:

1458710

Hom.:

22156

Cov.:

AF XY:

0.161

AC XY:

117149

AN XY:

725892

show subpopulations

Gnomad4 AFR exome

AF:

0.389

Gnomad4 AMR exome

AF:

0.279

Gnomad4 ASJ exome

AF:

0.167

Gnomad4 EAS exome

AF:

0.162

Gnomad4 SAS exome

AF:

0.0800

Gnomad4 FIN exome

AF:

0.125

Gnomad4 NFE exome

AF:

0.164

Gnomad4 OTH exome

AF:

0.169

GnomAD4 genome

AF:

0.219

AC:

33291

AN:

152084

Hom.:

4645

Cov.:

AF XY:

0.216

AC XY:

16046

AN XY:

74330

show subpopulations

Gnomad4 AFR

AF:

0.380

Gnomad4 AMR

AF:

0.225

Gnomad4 ASJ

AF:

0.170

Gnomad4 EAS

AF:

0.174

Gnomad4 SAS

AF:

0.0760

Gnomad4 FIN

AF:

0.126

Gnomad4 NFE

AF:

0.152

Gnomad4 OTH

AF:

0.186

Alfa

AF:

0.164

Hom.:

5079

Bravo

AF:

0.241

TwinsUK

AF:

0.176

AC:

651

ALSPAC

AF:

0.168

AC:

649

ESP6500AA

AF:

0.382

AC:

1684

ESP6500EA

AF:

0.165

AC:

1415

ExAC

AF:

0.174

AC:

21145

Asia WGS

AF:

0.121

AC:

420

AN:

3478

EpiCase

AF:

0.153

EpiControl

AF:

0.158

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3Other:1

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

- -

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

Nov 12, 2023

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 39% of patients studied by a panel of primary immunodeficiencies. Number of patients: 37. Only high quality variants are reported. -

Oct 31, 2013

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:3

May 02, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 25, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.40

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Benign

0.33

T;T;T;.;.;.

Eigen

Benign

-0.12

Eigen_PC

Benign

0.050

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.64

.;T;T;T;T;T

MetaRNN

Benign

0.0021

T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.69

N;N;.;.;.;.

PrimateAI

Pathogenic

0.79

PROVEAN

Benign

-0.44

N;N;N;N;N;N

REVEL

Benign

0.086

Sift

Benign

0.45

T;T;T;T;T;T

Sift4G

Benign

0.22

T;T;T;T;T;T

Polyphen

0.0

B;B;.;.;B;B

Vest4

0.12

MutPred

0.14

Loss of disorder (P = 0.0549);Loss of disorder (P = 0.0549);.;.;.;.;

MPC

1.2

ClinPred

0.013

GERP RS

4.3

Varity_R

0.40

gMVP

0.55

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