rs1057519757

Variant names:

• chr5-68293310-G-A
• rs1057519757
• NM_181523.3:c.1126G>A
• PIK3R1 p.Gly376Arg

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PS3 PM2 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. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). ClinVar reports functional evidence for this variant: "SCV001478395: "Well-established models demonstrating downstream impact of the variant on RNA structure, gene expression, or protein function [PS3]"".

• Frequency: Genomes: not found (cov: 32)
• Consequence: PIK3R1 NM_181523.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: 10.0
• Publications: 78 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 11 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV001478395: "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
• 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 VariationId is 376064.Status of the report is no_assertion_criteria_provided, 0 stars.

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.1126G>A	p.Gly376Arg	missense	Exon 10 of 16	NP_852664.1	A0A2X0SFG1
	PIK3R1	NM_181504.4		c.316G>A	p.Gly106Arg	missense	Exon 4 of 10	NP_852556.2
	PIK3R1	NM_181524.2		c.226G>A	p.Gly76Arg	missense	Exon 4 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.1126G>A	p.Gly376Arg	missense	Exon 10 of 16	ENSP00000428056.1	P27986-1
	PIK3R1	ENST00000336483.10	TSL:1	c.316G>A	p.Gly106Arg	missense	Exon 4 of 10	ENSP00000338554.5	P27986-2
	PIK3R1	ENST00000320694.13	TSL:1	c.226G>A	p.Gly76Arg	missense	Exon 4 of 10	ENSP00000323512.8	P27986-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

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

Computational scores

Source: dbNSFP v4.9

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
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.69	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.7	M
PhyloP100		10
PrimateAI	Pathogenic	0.94	D
PROVEAN	Pathogenic	-7.4	D
REVEL	Pathogenic	0.78
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.96
gMVP		0.82
Mutation Taster		=6/94	disease causing (ClinVar)

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

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

Other links and lift over

dbSNP: rs1057519757;

hg19: chr5-67589138;

COSMIC: COSV57123316;

COSMIC: COSV57123316;