rs171649

Positions:

• chr5-68273918-G-A
• chr5-68273918-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_181523.3(PIK3R1):​c.428-21G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.362 in 1,597,208 control chromosomes in the GnomAD database, including 109,233 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.29 (8116 hom., cov: 31)
  • Exomes 𝑓: 0.37 (101117 hom.)
• Consequence: PIK3R1 NM_181523.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.138

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: This place is a probable branch point but rather VUS (scored 4 / 10). Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BP6: Variant 5-68273918-G-A is Benign according to our data. Variant chr5-68273918-G-A is described in ClinVar as [Benign]. Clinvar id is 1271646.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.379 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PIK3R1	NM_181523.3	c.428-21G>A		intron_variant		ENST00000521381.6	NP_852664.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PIK3R1	ENST00000521381.6	c.428-21G>A		intron_variant		1	NM_181523.3	ENSP00000428056.1

Frequencies

GnomAD3 genomes AF: 0.294 AC: 44694 AN: 151964 Hom.: 8120 Cov.: 31

Gnomad AFR AF: 0.0735

Gnomad AMI AF: 0.381

Gnomad AMR AF: 0.355

Gnomad ASJ AF: 0.353

Gnomad EAS AF: 0.361

Gnomad SAS AF: 0.377

Gnomad FIN AF: 0.399

Gnomad MID AF: 0.307

Gnomad NFE AF: 0.383

Gnomad OTH AF: 0.302

GnomAD3 exomes AF: 0.363 AC: 91016 AN: 250972 Hom.: 17431 AF XY: 0.367 AC XY: 49738 AN XY: 135618

Gnomad AFR exome AF: 0.0698

Gnomad AMR exome AF: 0.399

Gnomad ASJ exome AF: 0.352

Gnomad EAS exome AF: 0.348

Gnomad SAS exome AF: 0.374

Gnomad FIN exome AF: 0.405

Gnomad NFE exome AF: 0.385

Gnomad OTH exome AF: 0.365

GnomAD4 exome AF: 0.370 AC: 533983 AN: 1445124 Hom.: 101117 Cov.: 28 AF XY: 0.371 AC XY: 267106 AN XY: 720022

Gnomad4 AFR exome AF: 0.0612

Gnomad4 AMR exome AF: 0.395

Gnomad4 ASJ exome AF: 0.353

Gnomad4 EAS exome AF: 0.380

Gnomad4 SAS exome AF: 0.376

Gnomad4 FIN exome AF: 0.408

Gnomad4 NFE exome AF: 0.377

Gnomad4 OTH exome AF: 0.352

GnomAD4 genome AF: 0.294 AC: 44679 AN: 152084 Hom.: 8116 Cov.: 31 AF XY: 0.297 AC XY: 22060 AN XY: 74344

Gnomad4 AFR AF: 0.0733

Gnomad4 AMR AF: 0.355

Gnomad4 ASJ AF: 0.353

Gnomad4 EAS AF: 0.361

Gnomad4 SAS AF: 0.376

Gnomad4 FIN AF: 0.399

Gnomad4 NFE AF: 0.383

Gnomad4 OTH AF: 0.303

Alfa AF: 0.349 Hom.: 2328

Bravo AF: 0.280

Asia WGS AF: 0.338 AC: 1174 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 31, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Nov 12, 2023

This variant is classified as Benign based on local population frequency. This variant was detected in 61% of patients studied by a panel of primary immunodeficiencies. Number of patients: 59. Only high quality variants are reported. -

Agammaglobulinemia 7, autosomal recessive Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 05, 2021

- -

SHORT syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 05, 2021

- -

Immunodeficiency 36 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 05, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	7.9
DANN	Benign	0.90
BranchPoint Hunter		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs171649; hg19: chr5-67569746; COSMIC: COSV57122901; COSMIC: COSV57122901;