rs1131692243

Variant names:

• chr5-68295418-AGGT-A
• rs1131692243
• NM_181523.3:c.1748_1750delGGT

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PVS1 PS3 PM2 PP5

The ENST00000521381.6(PIK3R1):​c.1746-1_1747delGGT​(p.Trp583fs) variant causes a frameshift, splice acceptor, splice region, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars). ClinVar reports functional evidence for this variant: "SCV001478403: is supported by well-established models demonstrating downstream impact of the variant on RNA structure, gene expression, or protein function [PS3],". Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PIK3R1 ENST00000521381.6 frameshift, splice_acceptor, splice_region, intron
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 10.0
• Publications: 8 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)
• PIK3R1-related immunodeficiency and SHORT syndrome

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

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

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P, 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: Pathogenic. The variant received 15 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV001478403: is supported by well-established models demonstrating downstream impact of the variant on RNA structure, gene expression, or protein function [PS3],
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-68295418-AGGT-A is Pathogenic according to our data. Variant chr5-68295418-AGGT-A is described in ClinVar as Pathogenic. ClinVar VariationId is 376263.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000521381.6. 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.1748_1750delGGT	p.Trp583del	disruptive_inframe_deletion splice_region	Exon 14 of 16	NP_852664.1	A0A2X0SFG1
	PIK3R1	NM_181504.4		c.938_940delGGT	p.Trp313del	disruptive_inframe_deletion splice_region	Exon 8 of 10	NP_852556.2
	PIK3R1	NM_181524.2		c.848_850delGGT	p.Trp283del	disruptive_inframe_deletion splice_region	Exon 8 of 10	NP_852665.1	P27986-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIK3R1	ENST00000521381.6	TSL:1 MANE Select	c.1746-1_1747delGGT	p.Trp583fs	frameshift splice_acceptor splice_region intron	Exon 14 of 16	ENSP00000428056.1	P27986-1
	PIK3R1	ENST00000336483.10	TSL:1	c.936-1_937delGGT	p.Trp313fs	frameshift splice_acceptor splice_region intron	Exon 8 of 10	ENSP00000338554.5	P27986-2
	PIK3R1	ENST00000320694.13	TSL:1	c.846-1_847delGGT	p.Trp283fs	frameshift splice_acceptor splice_region intron	Exon 8 of 10	ENSP00000323512.8	P27986-3

Frequencies

GnomAD3 genomes Cov.: 32

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

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Vascular Malformations and Overgrowth (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		10

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_AG_spliceai		1.0		Position offset: 5
DS_AL_spliceai		1.0		Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs1131692243;

hg19: chr5-67591246;

COSMIC: COSV57130827;

COSMIC: COSV57130827;