chr5-68300260-G-A

Variant names:

• chr5-68300260-G-A
• rs3756668
• NM_181523.3:c.*2659G>A

Variant summary

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

The NM_181523.3(PIK3R1):​c.*2659G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.544 in 232,832 control chromosomes in the GnomAD database, including 38,076 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 0.58 (28697 hom., cov: 32)
  • Exomes 𝑓: 0.47 (9379 hom.)
• Consequence: PIK3R1 NM_181523.3 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.45
• Publications: 47 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=-0.88).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.888 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIK3R1	NM_181523.3	c.*2659G>A		3_prime_UTR_variant	Exon 16 of 16	ENST00000521381.6	NP_852664.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PIK3R1	ENST00000521381.6	c.*2659G>A		3_prime_UTR_variant	Exon 16 of 16	1	NM_181523.3	ENSP00000428056.1

Frequencies

GnomAD3 genomes AF: 0.581 AC: 88262 AN: 151994 Hom.: 28622 Cov.: 32

Gnomad AFR AF: 0.895

Gnomad AMI AF: 0.391

Gnomad AMR AF: 0.558

Gnomad ASJ AF: 0.471

Gnomad EAS AF: 0.482

Gnomad SAS AF: 0.478

Gnomad FIN AF: 0.433

Gnomad MID AF: 0.455

Gnomad NFE AF: 0.442

Gnomad OTH AF: 0.534

GnomAD4 exome AF: 0.472 AC: 38139 AN: 80720 Hom.: 9379 Cov.: 0 AF XY: 0.468 AC XY: 17362 AN XY: 37082

African (AFR) AF: 0.886 AC: 3444 AN: 3886

American (AMR) AF: 0.591 AC: 1470 AN: 2488

Ashkenazi Jewish (ASJ) AF: 0.461 AC: 2352 AN: 5106

East Asian (EAS) AF: 0.408 AC: 4628 AN: 11352

South Asian (SAS) AF: 0.474 AC: 331 AN: 698

European-Finnish (FIN) AF: 0.534 AC: 31 AN: 58

Middle Eastern (MID) AF: 0.419 AC: 206 AN: 492

European-Non Finnish (NFE) AF: 0.445 AC: 22204 AN: 49888

Other (OTH) AF: 0.514 AC: 3473 AN: 6752

GnomAD4 genome AF: 0.581 AC: 88411 AN: 152112 Hom.: 28697 Cov.: 32 AF XY: 0.578 AC XY: 42958 AN XY: 74352

African (AFR) AF: 0.896 AC: 37196 AN: 41528

American (AMR) AF: 0.559 AC: 8549 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.471 AC: 1636 AN: 3472

East Asian (EAS) AF: 0.481 AC: 2488 AN: 5168

South Asian (SAS) AF: 0.478 AC: 2305 AN: 4820

European-Finnish (FIN) AF: 0.433 AC: 4572 AN: 10548

Middle Eastern (MID) AF: 0.469 AC: 137 AN: 292

European-Non Finnish (NFE) AF: 0.442 AC: 30036 AN: 67966

Other (OTH) AF: 0.537 AC: 1136 AN: 2114

Alfa AF: 0.492 Hom.: 66546

Bravo AF: 0.604

Asia WGS AF: 0.564 AC: 1962 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.025
DANN	Benign	0.83
PhyloP100		-2.5
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: rs3756668; hg19: chr5-67596088;