5-68279814-A-G

Variant names:

• chr5-68279814-A-G
• rs3815701
• NM_181523.3:c.634+81A>G

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.634+81A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.236 in 1,361,854 control chromosomes in the GnomAD database, including 38,821 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (4194 hom., cov: 31)
  • Exomes 𝑓: 0.24 (34627 hom.)
• Consequence: PIK3R1 NM_181523.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.227
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 5-68279814-A-G is Benign according to our data. Variant chr5-68279814-A-G is described in ClinVar as [Benign]. Clinvar id is 1274836.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.244 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIK3R1	NM_181523.3	c.634+81A>G		intron_variant	Intron 5 of 15	ENST00000521381.6	NP_852664.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PIK3R1	ENST00000521381.6	c.634+81A>G		intron_variant	Intron 5 of 15	1	NM_181523.3	ENSP00000428056.1

Frequencies

GnomAD3 genomes AF: 0.232 AC: 35217 AN: 151948 Hom.: 4188 Cov.: 31

Gnomad AFR AF: 0.216

Gnomad AMI AF: 0.231

Gnomad AMR AF: 0.248

Gnomad ASJ AF: 0.237

Gnomad EAS AF: 0.167

Gnomad SAS AF: 0.255

Gnomad FIN AF: 0.241

Gnomad MID AF: 0.174

Gnomad NFE AF: 0.240

Gnomad OTH AF: 0.227

GnomAD4 exome AF: 0.236 AC: 285750 AN: 1209786 Hom.: 34627 AF XY: 0.236 AC XY: 144439 AN XY: 611088

African (AFR) AF: 0.211 AC: 5788 AN: 27450

American (AMR) AF: 0.227 AC: 8701 AN: 38352

Ashkenazi Jewish (ASJ) AF: 0.222 AC: 5073 AN: 22860

East Asian (EAS) AF: 0.151 AC: 5754 AN: 38008

South Asian (SAS) AF: 0.250 AC: 18827 AN: 75338

European-Finnish (FIN) AF: 0.247 AC: 12539 AN: 50854

Middle Eastern (MID) AF: 0.168 AC: 862 AN: 5126

European-Non Finnish (NFE) AF: 0.240 AC: 215790 AN: 900174

Other (OTH) AF: 0.241 AC: 12416 AN: 51624

GnomAD4 genome AF: 0.232 AC: 35255 AN: 152068 Hom.: 4194 Cov.: 31 AF XY: 0.231 AC XY: 17209 AN XY: 74340

African (AFR) AF: 0.216 AC: 8958 AN: 41444

American (AMR) AF: 0.248 AC: 3789 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.237 AC: 822 AN: 3470

East Asian (EAS) AF: 0.166 AC: 860 AN: 5172

South Asian (SAS) AF: 0.256 AC: 1233 AN: 4822

European-Finnish (FIN) AF: 0.241 AC: 2545 AN: 10578

Middle Eastern (MID) AF: 0.163 AC: 48 AN: 294

European-Non Finnish (NFE) AF: 0.240 AC: 16299 AN: 67980

Other (OTH) AF: 0.232 AC: 490 AN: 2112

Alfa AF: 0.232 Hom.: 13896

Bravo AF: 0.228

Asia WGS AF: 0.265 AC: 921 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jul 07, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

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 41% of patients studied by a panel of primary immunodeficiencies. Number of patients: 39. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	2.0
DANN	Benign	0.75
PhyloP100		-0.23
PromoterAI		-0.0098	Neutral
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: rs3815701; hg19: chr5-67575642; COSMIC: COSV57127033; COSMIC: COSV57127033;