rs373779625

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_005026.5(PIK3CD):​c.1379G>A​(p.Arg460His) variant causes a missense change. The variant allele was found at a frequency of 0.0001 in 1,613,202 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R460C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00010 ( 0 hom. )

Consequence

PIK3CD
NM_005026.5 missense

Scores

19

Clinical Significance

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

Conservation

PhyloP100: 5.48
Variant links:
Genes affected
PIK3CD (HGNC:8977): (phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta) Phosphoinositide 3-kinases (PI3Ks) phosphorylate inositol lipids and are involved in the immune response. The protein encoded by this gene is a class I PI3K found primarily in leukocytes. Like other class I PI3Ks (p110-alpha p110-beta, and p110-gamma), the encoded protein binds p85 adapter proteins and GTP-bound RAS. However, unlike the other class I PI3Ks, this protein phosphorylates itself, not p85 protein.[provided by RefSeq, Jul 2010]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.102909416).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PIK3CDNM_005026.5 linkc.1379G>A p.Arg460His missense_variant Exon 11 of 24 ENST00000377346.9 NP_005017.3 O00329-1A0A2K8FKV1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PIK3CDENST00000377346.9 linkc.1379G>A p.Arg460His missense_variant Exon 11 of 24 1 NM_005026.5 ENSP00000366563.4 O00329-1

Frequencies

GnomAD3 genomes
AF:
0.0000657
AC:
10
AN:
152198
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000724
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000193
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000735
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000319
AC:
8
AN:
250660
Hom.:
0
AF XY:
0.0000516
AC XY:
7
AN XY:
135732
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000109
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000442
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000103
AC:
151
AN:
1460886
Hom.:
0
Cov.:
33
AF XY:
0.000103
AC XY:
75
AN XY:
726766
show subpopulations
Gnomad4 AFR exome
AF:
0.000149
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000504
Gnomad4 SAS exome
AF:
0.0000348
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000123
Gnomad4 OTH exome
AF:
0.0000497
GnomAD4 genome
AF:
0.0000722
AC:
11
AN:
152316
Hom.:
0
Cov.:
32
AF XY:
0.0000537
AC XY:
4
AN XY:
74474
show subpopulations
Gnomad4 AFR
AF:
0.0000721
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000193
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000735
Gnomad4 OTH
AF:
0.000473
Alfa
AF:
0.0000386
Hom.:
0
Bravo
AF:
0.0000567
ESP6500AA
AF:
0.000227
AC:
1
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.0000247
AC:
3
EpiCase
AF:
0.000164
EpiControl
AF:
0.000119

ClinVar

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

Submissions by phenotype

Immunodeficiency 14 Uncertain:2
Aug 24, 2022
Genetics and Molecular Pathology, SA Pathology
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Apr 29, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 460 of the PIK3CD protein (p.Arg460His). This variant is present in population databases (rs373779625, gnomAD 0.005%). This variant has not been reported in the literature in individuals affected with PIK3CD-related conditions. ClinVar contains an entry for this variant (Variation ID: 541082). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PIK3CD protein function. 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. -

Inborn genetic diseases Uncertain:1
May 10, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.1379G>A (p.R460H) alteration is located in exon 11 (coding exon 9) of the PIK3CD gene. This alteration results from a G to A substitution at nucleotide position 1379, causing the arginine (R) at amino acid position 460 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.070
BayesDel_addAF
Benign
-0.17
T
BayesDel_noAF
Benign
-0.31
CADD
Benign
18
DANN
Benign
0.80
DEOGEN2
Benign
0.020
.;T;T;.;T
Eigen
Benign
-0.32
Eigen_PC
Benign
-0.19
FATHMM_MKL
Benign
0.58
D
LIST_S2
Benign
0.81
.;T;T;T;.
M_CAP
Benign
0.039
D
MetaRNN
Benign
0.10
T;T;T;T;T
MetaSVM
Benign
-0.58
T
MutationAssessor
Benign
-0.14
.;.;N;.;.
PrimateAI
Benign
0.29
T
PROVEAN
Benign
-1.0
N;.;N;.;N
REVEL
Benign
0.21
Sift
Benign
0.16
T;.;T;.;T
Sift4G
Benign
0.15
T;T;T;T;T
Polyphen
0.0090
B;.;B;B;.
Vest4
0.25
MVP
0.72
MPC
1.1
ClinPred
0.068
T
GERP RS
4.6
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.2
Varity_R
0.080
gMVP
0.62

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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: rs373779625; hg19: chr1-9780209; COSMIC: COSV63128393; COSMIC: COSV63128393; API