rs706716

Variant names:

• chr5-68252614-C-T
• rs706716
• NM_181523.3:c.335-20776C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_181523.3(PIK3R1):​c.335-20776C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.19 in 152,082 control chromosomes in the GnomAD database, including 3,398 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.19 (3398 hom., cov: 32)
• Consequence: PIK3R1 NM_181523.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.238
• Publications: 14 publications found

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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.254 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIK3R1	NM_181523.3	c.335-20776C>T		intron_variant	Intron 2 of 15	ENST00000521381.6	NP_852664.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PIK3R1	ENST00000521381.6	c.335-20776C>T		intron_variant	Intron 2 of 15	1	NM_181523.3	ENSP00000428056.1

Frequencies

GnomAD3 genomes AF: 0.190 AC: 28927 AN: 151964 Hom.: 3399 Cov.: 32

Gnomad AFR AF: 0.0498

Gnomad AMI AF: 0.267

Gnomad AMR AF: 0.227

Gnomad ASJ AF: 0.245

Gnomad EAS AF: 0.179

Gnomad SAS AF: 0.207

Gnomad FIN AF: 0.225

Gnomad MID AF: 0.259

Gnomad NFE AF: 0.257

Gnomad OTH AF: 0.205

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.190 AC: 28922 AN: 152082 Hom.: 3398 Cov.: 32 AF XY: 0.189 AC XY: 14078 AN XY: 74322

African (AFR) AF: 0.0496 AC: 2060 AN: 41502

American (AMR) AF: 0.227 AC: 3477 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.245 AC: 849 AN: 3466

East Asian (EAS) AF: 0.179 AC: 927 AN: 5170

South Asian (SAS) AF: 0.207 AC: 998 AN: 4816

European-Finnish (FIN) AF: 0.225 AC: 2376 AN: 10550

Middle Eastern (MID) AF: 0.259 AC: 76 AN: 294

European-Non Finnish (NFE) AF: 0.257 AC: 17487 AN: 67970

Other (OTH) AF: 0.203 AC: 429 AN: 2114

Alfa AF: 0.222 Hom.: 4626

Bravo AF: 0.186

Asia WGS AF: 0.163 AC: 568 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	2.5
DANN	Benign	0.66
PhyloP100		-0.24
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs706716; hg19: chr5-67548442; COSMIC: COSV57126869;