rs540361957

chr5-68280542-G-Achr5-68280542-G-Cchr5-68280542-G-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 1P and 7B. PP2BP4_ModerateBS1_SupportingBS2

The NM_181523.3(PIK3R1):c.649G>A(p.Glu217Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000452 in 1,591,990 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000049 ( 4 hom. )

Consequence

PIK3R1
NM_181523.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 7.44

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_benign. Variant got -6 ACMG points.

PP2

Missense variant where missense usually causes diseases, PIK3R1

BP4

Computational evidence support a benign effect (MetaRNN=0.09048909).

BS1

Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.0000486 (70/1441706) while in subpopulation SAS AF= 0.000595 (51/85696). AF 95% confidence interval is 0.000465. There are 4 homozygotes in gnomad4_exome. There are 54 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAdExome at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PIK3R1	NM_181523.3 linkuse as main transcript	c.649G>A	p.Glu217Lys	missense_variant	6/16	ENST00000521381.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PIK3R1	ENST00000521381.6 linkuse as main transcript	c.649G>A	p.Glu217Lys	missense_variant	6/16	1	NM_181523.3	P1	P27986-1

Frequencies

GnomAD3 genomes

AF:

0.0000200

AC:

AN:

150166

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000133

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000211

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000880

AC:

AN:

249860

Hom.:

AF XY:

0.000140

AC XY:

AN XY:

135274

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000721

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000486

AC:

AN:

1441706

Hom.:

Cov.:

AF XY:

0.0000752

AC XY:

AN XY:

718250

show subpopulations

Gnomad4 AFR exome

AF:

0.0000907

Gnomad4 AMR exome

AF:

0.0000449

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000595

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000119

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000133

AC:

AN:

150284

Hom.:

Cov.:

AF XY:

0.0000137

AC XY:

AN XY:

73210

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000662

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000211

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ExAC

AF:

0.0000494

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Agammaglobulinemia 7, autosomal recessive

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center

Mar 29, 2024

- -

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 10, 2023

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 217 of the PIK3R1 protein (p.Glu217Lys). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. ClinVar contains an entry for this variant (Variation ID: 576303). This missense change has been observed in individual(s) with clinical features of activated PI3K delta syndrome (PMID: 34922003). This variant is present in population databases (rs540361957, gnomAD 0.07%). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.082

BayesDel_noAF

Benign

-0.36

Cadd

Pathogenic

Dann

Uncertain

1.0

DEOGEN2

Benign

0.17

T;T;T

Eigen

Uncertain

0.38

Eigen_PC

Uncertain

0.47

FATHMM_MKL

Pathogenic

0.99

M_CAP

Benign

0.0086

MetaRNN

Benign

0.090

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.9

L;L;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Benign

0.43

PROVEAN

Benign

-1.1

N;N;N

REVEL

Benign

0.15

Sift

Benign

0.15

T;T;D

Sift4G

Benign

0.21

T;T;D

Polyphen

0.83

P;P;.

Vest4

0.30

MutPred

0.56

Gain of ubiquitination at E217 (P = 0.0155);Gain of ubiquitination at E217 (P = 0.0155);.;

MVP

0.46

MPC

0.14

ClinPred

0.25

GERP RS

4.7

Varity_R

0.34

gMVP

0.33

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