5-68296453-G-A

Variant names:

• chr5-68296453-G-A
• rs895304
• NM_181523.3:c.1985+112G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_181523.3(PIK3R1):​c.1985+112G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.2 in 990,694 control chromosomes in the GnomAD database, including 22,577 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.25 (5686 hom., cov: 32)
  • Exomes 𝑓: 0.19 (16891 hom.)
• Consequence: PIK3R1 NM_181523.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.197
• Publications: 13 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 5-68296453-G-A is Benign according to our data. Variant chr5-68296453-G-A is described in ClinVar as Benign. ClinVar VariationId is 1261654.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.404 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_181523.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIK3R1	NM_181523.3	MANE Select	c.1985+112G>A		intron	N/A	NP_852664.1
	PIK3R1	NM_181504.4		c.1175+112G>A		intron	N/A	NP_852556.2
	PIK3R1	NM_181524.2		c.1085+112G>A		intron	N/A	NP_852665.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIK3R1	ENST00000521381.6	TSL:1 MANE Select	c.1985+112G>A		intron	N/A	ENSP00000428056.1
	PIK3R1	ENST00000336483.10	TSL:1	c.1175+112G>A		intron	N/A	ENSP00000338554.5
	PIK3R1	ENST00000320694.13	TSL:1	c.1085+112G>A		intron	N/A	ENSP00000323512.8

Frequencies

GnomAD3 genomes AF: 0.247 AC: 37574 AN: 151920 Hom.: 5678 Cov.: 32

Gnomad AFR AF: 0.410

Gnomad AMI AF: 0.141

Gnomad AMR AF: 0.247

Gnomad ASJ AF: 0.202

Gnomad EAS AF: 0.343

Gnomad SAS AF: 0.213

Gnomad FIN AF: 0.139

Gnomad MID AF: 0.215

Gnomad NFE AF: 0.165

Gnomad OTH AF: 0.223

GnomAD4 exome AF: 0.192 AC: 160772 AN: 838656 Hom.: 16891 AF XY: 0.189 AC XY: 80855 AN XY: 426798

African (AFR) AF: 0.419 AC: 8572 AN: 20474

American (AMR) AF: 0.282 AC: 7171 AN: 25438

Ashkenazi Jewish (ASJ) AF: 0.203 AC: 3383 AN: 16640

East Asian (EAS) AF: 0.312 AC: 11233 AN: 35954

South Asian (SAS) AF: 0.199 AC: 11233 AN: 56472

European-Finnish (FIN) AF: 0.139 AC: 6229 AN: 44936

Middle Eastern (MID) AF: 0.182 AC: 654 AN: 3588

European-Non Finnish (NFE) AF: 0.175 AC: 104162 AN: 596136

Other (OTH) AF: 0.208 AC: 8135 AN: 39018

GnomAD4 genome AF: 0.247 AC: 37623 AN: 152038 Hom.: 5686 Cov.: 32 AF XY: 0.247 AC XY: 18326 AN XY: 74332

African (AFR) AF: 0.409 AC: 16952 AN: 41410

American (AMR) AF: 0.248 AC: 3782 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.202 AC: 700 AN: 3468

East Asian (EAS) AF: 0.343 AC: 1776 AN: 5178

South Asian (SAS) AF: 0.213 AC: 1028 AN: 4826

European-Finnish (FIN) AF: 0.139 AC: 1470 AN: 10564

Middle Eastern (MID) AF: 0.231 AC: 68 AN: 294

European-Non Finnish (NFE) AF: 0.165 AC: 11249 AN: 68002

Other (OTH) AF: 0.222 AC: 469 AN: 2110

Alfa AF: 0.201 Hom.: 6928

Bravo AF: 0.268

Asia WGS AF: 0.298 AC: 1035 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Jun 26, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:1

Jan 24, 2024

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 23% of patients studied by a panel of primary immunodeficiencies. Number of patients: 22. Only high quality variants are reported.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.47
DANN	Benign	0.17
PhyloP100		-0.20
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: rs895304; hg19: chr5-67592281; COSMIC: COSV57136851; COSMIC: COSV57136851;