rs251406

Variant names:

• chr5-68240633-A-G
• rs251406
• NM_181523.3:c.334+13624A>G

Variant summary

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

The NM_181523.3(PIK3R1):​c.334+13624A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.742 in 152,140 control chromosomes in the GnomAD database, including 42,070 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 0.74 (42070 hom., cov: 32)
• Consequence: PIK3R1 NM_181523.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.27
• Publications: 9 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=-0.74).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.905 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.334+13624A>G		intron	N/A	NP_852664.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIK3R1	ENST00000521381.6	TSL:1 MANE Select	c.334+13624A>G		intron	N/A	ENSP00000428056.1
	PIK3R1	ENST00000517412.2	TSL:1	n.934+13624A>G		intron	N/A
	PIK3R1	ENST00000697461.1		c.334+13624A>G		intron	N/A	ENSP00000513319.1

Frequencies

GnomAD3 genomes AF: 0.742 AC: 112777 AN: 152022 Hom.: 42030 Cov.: 32

Gnomad AFR AF: 0.774

Gnomad AMI AF: 0.777

Gnomad AMR AF: 0.788

Gnomad ASJ AF: 0.681

Gnomad EAS AF: 0.927

Gnomad SAS AF: 0.690

Gnomad FIN AF: 0.714

Gnomad MID AF: 0.630

Gnomad NFE AF: 0.709

Gnomad OTH AF: 0.729

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.742 AC: 112866 AN: 152140 Hom.: 42070 Cov.: 32 AF XY: 0.743 AC XY: 55261 AN XY: 74370

African (AFR) AF: 0.773 AC: 32105 AN: 41510

American (AMR) AF: 0.788 AC: 12062 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.681 AC: 2358 AN: 3464

East Asian (EAS) AF: 0.927 AC: 4808 AN: 5186

South Asian (SAS) AF: 0.690 AC: 3324 AN: 4816

European-Finnish (FIN) AF: 0.714 AC: 7542 AN: 10564

Middle Eastern (MID) AF: 0.633 AC: 186 AN: 294

European-Non Finnish (NFE) AF: 0.709 AC: 48227 AN: 67984

Other (OTH) AF: 0.732 AC: 1545 AN: 2110

Alfa AF: 0.719 Hom.: 61361

Bravo AF: 0.752

Asia WGS AF: 0.806 AC: 2803 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	0.047
DANN	Benign	0.79
PhyloP100		-2.3
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs251406; hg19: chr5-67536461;