NM_181523.3:c.335-978C>G

Variant names:

• chr5-68272412-C-G
• rs831123
• NM_181523.3:c.335-978C>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.335-978C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0748 in 152,154 control chromosomes in the GnomAD database, including 538 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 0.075 (538 hom., cov: 32)
• Consequence: PIK3R1 NM_181523.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.29
• Publications: 3 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: Labcorp Genetics (formerly Invitae), Ambry Genetics
• PIK3R1-related immunodeficiency and SHORT syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• SHORT syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics, ClinGen
• agammaglobulinemia 7, autosomal recessive

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen
• 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=-0.86).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0992 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIK3R1	NM_181523.3	MANE Select	c.335-978C>G		intron	N/A	NP_852664.1	A0A2X0SFG1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIK3R1	ENST00000521381.6	TSL:1 MANE Select	c.335-978C>G		intron	N/A	ENSP00000428056.1	P27986-1
	PIK3R1	ENST00000517412.2	TSL:1	n.935-978C>G		intron	N/A
	PIK3R1	ENST00000697461.1		c.335-978C>G		intron	N/A	ENSP00000513319.1	P27986-4

Frequencies

GnomAD3 genomes AF: 0.0749 AC: 11394 AN: 152036 Hom.: 538 Cov.: 32

Gnomad AFR AF: 0.0216

Gnomad AMI AF: 0.0888

Gnomad AMR AF: 0.0671

Gnomad ASJ AF: 0.111

Gnomad EAS AF: 0.0808

Gnomad SAS AF: 0.0815

Gnomad FIN AF: 0.106

Gnomad MID AF: 0.0823

Gnomad NFE AF: 0.101

Gnomad OTH AF: 0.0796

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

GnomAD4 genome AF: 0.0748 AC: 11387 AN: 152154 Hom.: 538 Cov.: 32 AF XY: 0.0748 AC XY: 5565 AN XY: 74376

African (AFR) AF: 0.0215 AC: 894 AN: 41512

American (AMR) AF: 0.0669 AC: 1023 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.111 AC: 383 AN: 3466

East Asian (EAS) AF: 0.0810 AC: 420 AN: 5186

South Asian (SAS) AF: 0.0807 AC: 389 AN: 4818

European-Finnish (FIN) AF: 0.106 AC: 1121 AN: 10564

Middle Eastern (MID) AF: 0.0850 AC: 25 AN: 294

European-Non Finnish (NFE) AF: 0.101 AC: 6884 AN: 68002

Other (OTH) AF: 0.0792 AC: 167 AN: 2108

Alfa AF: 0.0926 Hom.: 92

Bravo AF: 0.0693

Asia WGS AF: 0.0580 AC: 203 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.66
DANN	Benign	0.62
PhyloP100		-1.3
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: rs831123; hg19: chr5-67568240;