NM_181523.3:c.1106C>T

Variant names:

• chr5-68293187-C-T
• rs587784325
• NM_181523.3:c.1106C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Moderate PP5_Moderate

The NM_181523.3(PIK3R1):​c.1106C>T​(p.Thr369Ile) 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. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PIK3R1 NM_181523.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.91
• Publications: 4 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), ClinGen
• SHORT syndrome

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

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• activated PI3K-delta syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• autosomal agammaglobulinemia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.92
• PP5: Variant 5-68293187-C-T is Pathogenic according to our data. Variant chr5-68293187-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 159719.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-68293187-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 159719.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-68293187-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 159719.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-68293187-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 159719.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-68293187-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 159719.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-68293187-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 159719.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-68293187-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 159719.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-68293187-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 159719.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-68293187-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 159719.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-68293187-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 159719.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-68293187-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 159719.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-68293187-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 159719.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-68293187-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 159719.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-68293187-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 159719.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-68293187-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 159719.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-68293187-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 159719.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-68293187-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 159719.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-68293187-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 159719.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-68293187-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 159719.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-68293187-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 159719.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-68293187-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 159719.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-68293187-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 159719.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-68293187-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 159719.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-68293187-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 159719.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-68293187-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 159719.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-68293187-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 159719.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-68293187-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 159719.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-68293187-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 159719.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-68293187-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 159719.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-68293187-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 159719.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-68293187-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 159719.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-68293187-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 159719.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIK3R1	NM_181523.3	c.1106C>T	p.Thr369Ile	missense_variant	Exon 9 of 16	ENST00000521381.6	NP_852664.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PIK3R1	ENST00000521381.6	c.1106C>T	p.Thr369Ile	missense_variant	Exon 9 of 16	1	NM_181523.3	ENSP00000428056.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Alfa AF: 0.00000536 Hom.: 0

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

SHORT syndrome Pathogenic:1

May 29, 2014

Genetic Services Laboratory, University of Chicago

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.88	D;D;D;.;.;D;.;D;.
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.99	.;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.59	D
MetaRNN	Pathogenic	0.92	D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.85	D
MutationAssessor	Uncertain	2.8	M;M;.;.;.;.;.;.;.
PhyloP100		7.9
PrimateAI	Pathogenic	0.93	D
PROVEAN	Pathogenic	-5.7	D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.0030	D;D;D;D;D;D;D;D;D
Polyphen		1.0	D;D;.;.;D;.;D;.;.
Vest4		0.73
MutPred		0.68		Loss of disorder (P = 0.0611);Loss of disorder (P = 0.0611);.;.;.;.;.;.;.;
MVP		0.98
MPC		2.4
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.97
gMVP		0.88
Mutation Taster		=13/87	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs587784325; hg19: chr5-67589015;