rs1131692243

Variant names:

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

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 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). 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

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]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• 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 id is 376263.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr5-68295418-AGGT-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIK3R1	NM_181523.3	c.1748_1750delGGT	p.Trp583del	disruptive_inframe_deletion, splice_region_variant	Exon 14 of 16	ENST00000521381.6	NP_852664.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PIK3R1	ENST00000521381.6	c.1746-1_1747delGGT	p.Trp583fs	frameshift_variant, splice_acceptor_variant, splice_region_variant, intron_variant	Exon 14 of 16	1	NM_181523.3	ENSP00000428056.1

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

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Vascular Malformations and Overgrowth Pathogenic:1

Nov 08, 2020

Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

This alteration is of apparent somatic mosaic etiology with strong supporting evidence including no discernible strand bias, in a region absent of repetition and sequence homology, with clean, high-quality reads, having a variant allele fraction >= 3% [PS2], is supported by well-established models demonstrating downstream impact of the variant on RNA structure, gene expression, or protein function [PS3], is either well-represented in cancer as identified in the COSMIC database with >=20 documented instances or considered to occur in a statistically significant hotspot or region according to cancerhotspots.org database [PM_CANCER], is in a non-repetitive region and results in a protein length change predicted to result in an in-frame protein product [PM4], and is at increased prevalence in our cohort, with >= 3 occurrences in unrelated individuals [PS4_Sup]. -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs1131692243; hg19: chr5-67591246;