rs1057519757

Positions:

• chr5-68293310-G-A
• chr5-68293310-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PP2 PP3_Strong PP5

The NM_181523.3(PIK3R1):​c.1126G>A​(p.Gly376Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PIK3R1 NM_181523.3 missense
• 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]

PIK3R1 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), PIK3R1. . Gene score misZ 2.7206 (greater than the threshold 3.09). Trascript score misZ 3.4358 (greater than threshold 3.09). GenCC has associacion of gene with agammaglobulinemia 7, autosomal recessive, autosomal agammaglobulinemia, immunodeficiency 36, SHORT syndrome, activated PI3K-delta syndrome.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.952
• PP5: Variant 5-68293310-G-A is Pathogenic according to our data. Variant chr5-68293310-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 376064.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr5-68293310-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PIK3R1	NM_181523.3	c.1126G>A	p.Gly376Arg	missense_variant	10/16	ENST00000521381.6	NP_852664.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PIK3R1	ENST00000521381.6	c.1126G>A	p.Gly376Arg	missense_variant	10/16	1	NM_181523.3	ENSP00000428056.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

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

Pathogenic, no assertion criteria provided

research

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

Nov 08, 2020

This alteration is both well-represented in cancer as identified in the COSMIC database with >=20 documented instances and also considered to occur in a statistically significant hotspot or region according to cancerhotspots.org database [PS_CANCER], is supported by well-established models demonstrating downstream impact of the variant on RNA structure, gene expression, or protein function [PS3], is of apparent somatic mosaic etiology with moderate 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_Mod], and is a missense variant in a gene that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease [PP2]. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.87	D;D;D;.;D;.;D;.
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.99	.;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.69	D
MetaRNN	Pathogenic	0.95	D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.7	M;M;.;.;.;.;.;.
PrimateAI	Pathogenic	0.94	D
PROVEAN	Pathogenic	-7.4	D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.78
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;T;D;D;D;D;D
Polyphen		1.0	D;D;.;D;.;D;.;.
Vest4		0.77
MutPred		0.81		Gain of solvent accessibility (P = 0.019);Gain of solvent accessibility (P = 0.019);.;.;.;.;.;.;
MVP		0.98
MPC		2.5
ClinPred		1.0	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.96
gMVP		0.82

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

Publications

LitVar

Other links and lift over

dbSNP: rs1057519757; hg19: chr5-67589138; COSMIC: COSV57123316; COSMIC: COSV57123316;