rs1057519841

chr5-68295269-A-Gchr5-68295269-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM5 PP2 PP5_Moderate

The NM_181523.3(PIK3R1):c.1690A>G(p.Asn564Asp) variant causes a missense change involving the alteration of a conserved nucleotide. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N564K) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PIK3R1 NM_181523.3 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:7
• Conservation: PhyloP100: 9.32

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 Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_181523.3
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr5-68295271-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 376067.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant where missense usually causes diseases, PIK3R1
• PP5: Variant 5-68295269-A-G is Pathogenic according to our data. Variant chr5-68295269-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 376261.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-68295269-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PIK3R1	NM_181523.3	c.1690A>G	p.Asn564Asp	missense_variant	13/16	ENST00000521381.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PIK3R1	ENST00000521381.6	c.1690A>G	p.Asn564Asp	missense_variant	13/16	1	NM_181523.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1461840 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727214

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, single submitter

Submissions by phenotype

Neoplasm Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

Jul 14, 2015

- -

Malignant neoplasm of body of uterus Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Neoplasm of brain Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Malignant melanoma of skin Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Vascular malformation Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Clinical Genomics Laboratory, Washington University in St. Louis

Sep 21, 2023

The PIK3R1 c.1690A>G (p.Asn564Asp) variant was identified at an allelic fraction consistent with somatic origin. It has been identified in numerous individuals with vascular anomalies and overgrowth (Cottrell et al., PMID: 34040190). This variant has been reported as a pathogenic somatic variant by a single submitter (ClinVar ID: 376261). It also has been reported in 55 cases in the cancer database (COSMIC ID: COSV57124003). PIK3R1 c.1690A>G (p.Asn564Asp) is absent from the general population (gnomAD v.3.1.2), indicating it is not a common variant. This variant resides within the helical domain, amino acids 525-696, of phosphatidylinositol 3-Kinase (PI3K) protein complex that is defined as a critical functional domain (Huang CH et al., PMID: 18079394). The PIK3R1 is a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (Cottrell et al., PMID: 34040190). Functional patient-derived cells studies show that this asparagine substitution at codon 564 leads to autonomous phosphorylation of AKT and activation of the downstream AKT-mTOR signaling, indicating that this variant impacts protein function (Jaiswal BS et al., PMID: 19962665; Urick ME et al., PMID: 21478295). Based on an internally-developed protocol informed by the ACMG/AMP guidelines (Richards S et al., PMID: 25741868) and gene-specific practices from the ClinGen Criteria Specification Registry, the PIK3R1 c.1690A>G (p.Asn564Asp) variant is classified as pathogenic. -

Neoplasm of the large intestine Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

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 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 at increased prevalence in our cohort, with >= 5 occurrences in unrelated individuals [PS4_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	Benign	-0.022	T
BayesDel_noAF	Benign	-0.27
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.81	D;D;.;.;.
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Benign	0.042	D
MetaRNN	Uncertain	0.59	D;D;D;D;D
MetaSVM	Benign	-0.70	T
MutationAssessor	Uncertain	2.2	M;M;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-3.4	D;D;D;D;D
REVEL	Uncertain	0.36
Sift	Uncertain	0.0050	D;D;D;D;D
Sift4G	Uncertain	0.016	D;D;D;D;D
Polyphen		0.93	P;P;B;B;.
Vest4		0.68
MutPred		0.28		Loss of MoRF binding (P = 0.0393);Loss of MoRF binding (P = 0.0393);.;.;.;
MVP		0.58
MPC		2.4
ClinPred		0.99	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.90
gMVP		0.76

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: rs1057519841; hg19: chr5-67591097; COSMIC: COSV57124003; COSMIC: COSV57124003;