chr5-68292303-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 3P and 3B. PM2PP2BP4_ModerateBS1_Supporting

The NM_181523.3(PIK3R1):​c.961G>A​(p.Gly321Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000502 in 1,613,394 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000052 ( 0 hom. )

Consequence

PIK3R1
NM_181523.3 missense

Scores

4
15

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 2.95
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), PIK3R1. . Gene score misZ 2.7206 (greater than the threshold 3.09). Trascript score misZ 3.4358 (greater than threshold 3.09). GenCC has associacion of gene with agammaglobulinemia 7, autosomal recessive, autosomal agammaglobulinemia, immunodeficiency 36, SHORT syndrome, activated PI3K-delta syndrome.
BP4
Computational evidence support a benign effect (MetaRNN=0.120363235).
BS1
Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.000052 (76/1461346) while in subpopulation NFE AF= 0.000063 (70/1111574). AF 95% confidence interval is 0.0000508. There are 0 homozygotes in gnomad4_exome. There are 37 alleles in male gnomad4_exome subpopulation. Median coverage is 29. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
PIK3R1NM_181523.3 linkuse as main transcriptc.961G>A p.Gly321Ser missense_variant 8/16 ENST00000521381.6 NP_852664.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
PIK3R1ENST00000521381.6 linkuse as main transcriptc.961G>A p.Gly321Ser missense_variant 8/161 NM_181523.3 ENSP00000428056 P1P27986-1

Frequencies

GnomAD3 genomes
AF:
0.0000329
AC:
5
AN:
152048
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000735
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000716
AC:
18
AN:
251334
Hom.:
0
AF XY:
0.0000810
AC XY:
11
AN XY:
135854
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000544
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.0000462
Gnomad NFE exome
AF:
0.000123
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.0000520
AC:
76
AN:
1461346
Hom.:
0
Cov.:
29
AF XY:
0.0000509
AC XY:
37
AN XY:
726988
show subpopulations
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:
0.0000348
Gnomad4 FIN exome
AF:
0.0000187
Gnomad4 NFE exome
AF:
0.0000630
Gnomad4 OTH exome
AF:
0.0000331
GnomAD4 genome
AF:
0.0000329
AC:
5
AN:
152048
Hom.:
0
Cov.:
33
AF XY:
0.0000404
AC XY:
3
AN XY:
74274
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000735
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000113
Hom.:
0
Bravo
AF:
0.0000378
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000233
AC:
2
ExAC
AF:
0.0000576
AC:
7
EpiCase
AF:
0.00
EpiControl
AF:
0.0000593

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

SHORT syndrome;C3554689:Agammaglobulinemia 7, autosomal recessive;C4014934:Immunodeficiency 36 Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpMay 23, 2023In 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. 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 not expected to disrupt PIK3R1 protein function. ClinVar contains an entry for this variant (Variation ID: 463170). This variant has not been reported in the literature in individuals affected with PIK3R1-related conditions. This variant is present in population databases (rs142439210, gnomAD 0.01%). This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 321 of the PIK3R1 protein (p.Gly321Ser). -
Uncertain significance, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsOct 31, 2018- -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenMay 01, 2022PIK3R1: PS4:Supporting, BP4 -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.089
BayesDel_addAF
Benign
-0.20
T
BayesDel_noAF
Benign
-0.30
CADD
Benign
21
DANN
Uncertain
0.98
DEOGEN2
Benign
0.31
T;T;T;.;.;.
Eigen
Benign
-0.30
Eigen_PC
Benign
-0.16
FATHMM_MKL
Uncertain
0.91
D
LIST_S2
Uncertain
0.90
.;D;D;D;D;D
M_CAP
Benign
0.022
T
MetaRNN
Benign
0.12
T;T;T;T;T;T
MetaSVM
Benign
-0.77
T
MutationAssessor
Benign
0.34
N;N;.;.;.;.
MutationTaster
Benign
1.0
D;D;D;D;D;D
PrimateAI
Uncertain
0.59
T
PROVEAN
Benign
-0.59
N;N;N;N;N;N
REVEL
Benign
0.20
Sift
Benign
0.41
T;T;T;T;T;T
Sift4G
Benign
0.40
T;T;T;T;T;T
Polyphen
0.0
B;B;.;.;B;B
Vest4
0.082
MVP
0.73
MPC
0.12
ClinPred
0.058
T
GERP RS
3.4
Varity_R
0.043
gMVP
0.49

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.

Other links and lift over

dbSNP: rs142439210; hg19: chr5-67588131; COSMIC: COSV99144224; COSMIC: COSV99144224; API