rs706713

Variant names:

• chr5-68226894-C-T
• rs706713
• NM_181523.3:c.219C>T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_181523.3(PIK3R1):​c.219C>T​(p.Tyr73Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.271 in 1,613,626 control chromosomes in the GnomAD database, including 66,189 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.31 (8330 hom., cov: 31)
  • Exomes 𝑓: 0.27 (57859 hom.)
• Consequence: PIK3R1 NM_181523.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10 O:1
• Conservation: PhyloP100: -3.30

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 5-68226894-C-T is Benign according to our data. Variant chr5-68226894-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 159722.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.3 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.669 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIK3R1	NM_181523.3	c.219C>T	p.Tyr73Tyr	synonymous_variant	Exon 2 of 16	ENST00000521381.6	NP_852664.1
PIK3R1	XM_005248542.4	c.219C>T	p.Tyr73Tyr	synonymous_variant	Exon 2 of 16		XP_005248599.1
PIK3R1	XM_017009585.3	c.219C>T	p.Tyr73Tyr	synonymous_variant	Exon 2 of 16		XP_016865074.1
PIK3R1	XM_047417315.1	c.219C>T	p.Tyr73Tyr	synonymous_variant	Exon 2 of 16		XP_047273271.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PIK3R1	ENST00000521381.6	c.219C>T	p.Tyr73Tyr	synonymous_variant	Exon 2 of 16	1	NM_181523.3	ENSP00000428056.1

Frequencies

GnomAD3 genomes AF: 0.314 AC: 47620 AN: 151712 Hom.: 8301 Cov.: 31

Gnomad AFR AF: 0.410

Gnomad AMI AF: 0.168

Gnomad AMR AF: 0.336

Gnomad ASJ AF: 0.200

Gnomad EAS AF: 0.688

Gnomad SAS AF: 0.325

Gnomad FIN AF: 0.265

Gnomad MID AF: 0.228

Gnomad NFE AF: 0.238

Gnomad OTH AF: 0.285

GnomAD3 exomes AF: 0.315 AC: 78832 AN: 250638 Hom.: 14537 AF XY: 0.305 AC XY: 41414 AN XY: 135752

Gnomad AFR exome AF: 0.413

Gnomad AMR exome AF: 0.392

Gnomad ASJ exome AF: 0.200

Gnomad EAS exome AF: 0.700

Gnomad SAS exome AF: 0.327

Gnomad FIN exome AF: 0.261

Gnomad NFE exome AF: 0.234

Gnomad OTH exome AF: 0.272

GnomAD4 exome AF: 0.267 AC: 389926 AN: 1461796 Hom.: 57859 Cov.: 35 AF XY: 0.266 AC XY: 193195 AN XY: 727212

Gnomad4 AFR exome AF: 0.420

Gnomad4 AMR exome AF: 0.388

Gnomad4 ASJ exome AF: 0.201

Gnomad4 EAS exome AF: 0.708

Gnomad4 SAS exome AF: 0.321

Gnomad4 FIN exome AF: 0.261

Gnomad4 NFE exome AF: 0.239

Gnomad4 OTH exome AF: 0.279

GnomAD4 genome AF: 0.314 AC: 47699 AN: 151830 Hom.: 8330 Cov.: 31 AF XY: 0.318 AC XY: 23571 AN XY: 74178

Gnomad4 AFR AF: 0.410

Gnomad4 AMR AF: 0.336

Gnomad4 ASJ AF: 0.200

Gnomad4 EAS AF: 0.688

Gnomad4 SAS AF: 0.326

Gnomad4 FIN AF: 0.265

Gnomad4 NFE AF: 0.238

Gnomad4 OTH AF: 0.292

Alfa AF: 0.252 Hom.: 8591

Bravo AF: 0.325

Asia WGS AF: 0.488 AC: 1697 AN: 3478

EpiCase AF: 0.228

EpiControl AF: 0.215

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3 Other:1

Jun 29, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 17016694) -

-

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant interpreted as Benign and reported on 04-27-2020 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. This variant was reported in an individual referred for clinical diagnostic genetic testing. -

Nov 23, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:3

Nov 12, 2023

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 54% of patients studied by a panel of primary immunodeficiencies. Number of patients: 52. Only high quality variants are reported. -

Oct 31, 2013

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

Agammaglobulinemia 7, autosomal recessive Benign:1

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

SHORT syndrome Benign:1

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

SHORT syndrome;C3554689:Agammaglobulinemia 7, autosomal recessive;C4014934:Immunodeficiency 36 Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Immunodeficiency 36 Benign:1

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	0.24
DANN	Benign	0.54

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

Other links and lift over

dbSNP: rs706713; hg19: chr5-67522722; COSMIC: COSV57124721; COSMIC: COSV57124721;