Genetic Variant PIK3R1:p.Leu466Val (chr5-68293805-T-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_181523.3(PIK3R1):c.1396T>G(p.Leu466Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000028 in 1,429,946 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. L466L) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000028 ( 0 hom. )

Consequence

PIK3R1
NM_181523.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.75

Publications

2 publications found

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 Gene-Disease associations (from GenCC):

immunodeficiency 36 with lymphoproliferation
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen
SHORT syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet
agammaglobulinemia 7, autosomal recessive
Inheritance: AR Classification: STRONG, LIMITED Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
activated PI3K-delta syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
autosomal agammaglobulinemia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

PIK3R1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIK3R1	NM_181523.3 link	c.1396T>G	p.Leu466Val	missense_variant	Exon 11 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.1396T>G	p.Leu466Val	missense_variant	Exon 11 of 16	1	NM_181523.3	ENSP00000428056.1		P27986-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000432

AC:

AN:

231540

AF XY:

0.00

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000917

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000280

AC:

AN:

1429946

Hom.:

Cov.:

AF XY:

0.00000281

AC XY:

AN XY:

711768

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32154

American (AMR)

AF:

0.00

AC:

AN:

38552

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25504

East Asian (EAS)

AF:

0.00

AC:

AN:

39224

South Asian (SAS)

AF:

0.00

AC:

AN:

80692

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53310

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5698

European-Non Finnish (NFE)

AF:

0.00000365

AC:

AN:

1095528

Other (OTH)

AF:

0.00

AC:

AN:

59284

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000508

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.74

BayesDel_addAF

Pathogenic

0.22

BayesDel_noAF

Uncertain

0.070

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.50

T;T;.;T;.;T;.

Eigen

Pathogenic

0.72

Eigen_PC

Uncertain

0.65

FATHMM_MKL

Uncertain

0.95

LIST_S2

Pathogenic

0.98

.;D;D;D;D;D;D

M_CAP

Uncertain

0.14

MetaRNN

Uncertain

0.62

D;D;D;D;D;D;D

MetaSVM

Uncertain

0.32

MutationAssessor

Uncertain

2.7

M;M;.;.;.;.;.

PhyloP100

4.8

PrimateAI

Uncertain

0.75

PROVEAN

Uncertain

-2.5

D;D;D;D;D;N;N

REVEL

Uncertain

0.46

Sift

Uncertain

0.0030

D;D;D;D;D;D;D

Sift4G

Uncertain

0.010

D;D;D;D;D;D;D

Polyphen

0.99

D;D;D;.;D;.;.

Vest4

0.49

MutPred

0.26

Loss of sheet (P = 0.0457);Loss of sheet (P = 0.0457);.;.;.;.;.;

MVP

0.91

MPC

1.9

ClinPred

0.92

GERP RS

4.0

Varity_R

0.70

gMVP

0.62

Mutation Taster

=14/86

disease causing

(source)

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

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5-68293805-T-G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

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