rs3730090

Variant names:

• chr5-68293360-C-T
• rs3730090
• NM_181523.3:c.1176C>T

Your query was ambiguous. Multiple possible variants found:

• chr5-68293360-C-T
• chr5-68293360-C-A
• chr5-68293360-C-G

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_181523.3(PIK3R1):​c.1176C>T​(p.Phe392Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0292 in 1,612,240 control chromosomes in the GnomAD database, including 2,139 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.053 (417 hom., cov: 32)
  • Exomes 𝑓: 0.027 (1722 hom.)
• Consequence: PIK3R1 NM_181523.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.50
• Publications: 25 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: Labcorp Genetics (formerly Invitae), Ambry Genetics
• PIK3R1-related immunodeficiency and SHORT syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• SHORT syndrome

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

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), 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: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.25).
• BP6: Variant 5-68293360-C-T is Benign according to our data. Variant chr5-68293360-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 159720.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.5 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.162 is higher than 0.05.

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.1176C>T	p.Phe392Phe	synonymous	Exon 10 of 16	NP_852664.1	A0A2X0SFG1
	PIK3R1	NM_181504.4		c.366C>T	p.Phe122Phe	synonymous	Exon 4 of 10	NP_852556.2
	PIK3R1	NM_181524.2		c.276C>T	p.Phe92Phe	synonymous	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.1176C>T	p.Phe392Phe	synonymous	Exon 10 of 16	ENSP00000428056.1	P27986-1
	PIK3R1	ENST00000336483.10	TSL:1	c.366C>T	p.Phe122Phe	synonymous	Exon 4 of 10	ENSP00000338554.5	P27986-2
	PIK3R1	ENST00000320694.13	TSL:1	c.276C>T	p.Phe92Phe	synonymous	Exon 4 of 10	ENSP00000323512.8	P27986-3

Frequencies

GnomAD3 genomes AF: 0.0525 AC: 7986 AN: 152126 Hom.: 418 Cov.: 32

Gnomad AFR AF: 0.110

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0338

Gnomad ASJ AF: 0.0346

Gnomad EAS AF: 0.172

Gnomad SAS AF: 0.138

Gnomad FIN AF: 0.0132

Gnomad MID AF: 0.0791

Gnomad NFE AF: 0.0137

Gnomad OTH AF: 0.0599

GnomAD2 exomes AF: 0.0530 AC: 13091 AN: 247096 AF XY: 0.0524

Gnomad AFR exome AF: 0.134

Gnomad AMR exome AF: 0.0272

Gnomad ASJ exome AF: 0.0419

Gnomad EAS exome AF: 0.175

Gnomad FIN exome AF: 0.0157

Gnomad NFE exome AF: 0.0198

Gnomad OTH exome AF: 0.0459

GnomAD4 exome AF: 0.0268 AC: 39059 AN: 1459996 Hom.: 1722 Cov.: 30 AF XY: 0.0293 AC XY: 21308 AN XY: 726370

African (AFR) AF: 0.120 AC: 3999 AN: 33418

American (AMR) AF: 0.0277 AC: 1240 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.0406 AC: 1061 AN: 26110

East Asian (EAS) AF: 0.154 AC: 6100 AN: 39626

South Asian (SAS) AF: 0.118 AC: 10142 AN: 86198

European-Finnish (FIN) AF: 0.0221 AC: 1169 AN: 52838

Middle Eastern (MID) AF: 0.0513 AC: 295 AN: 5756

European-Non Finnish (NFE) AF: 0.0112 AC: 12474 AN: 1111142

Other (OTH) AF: 0.0428 AC: 2579 AN: 60204

GnomAD4 genome AF: 0.0525 AC: 7994 AN: 152244 Hom.: 417 Cov.: 32 AF XY: 0.0531 AC XY: 3952 AN XY: 74440

African (AFR) AF: 0.110 AC: 4579 AN: 41544

American (AMR) AF: 0.0339 AC: 518 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0346 AC: 120 AN: 3468

East Asian (EAS) AF: 0.171 AC: 888 AN: 5178

South Asian (SAS) AF: 0.138 AC: 666 AN: 4814

European-Finnish (FIN) AF: 0.0132 AC: 140 AN: 10620

Middle Eastern (MID) AF: 0.0816 AC: 24 AN: 294

European-Non Finnish (NFE) AF: 0.0137 AC: 934 AN: 68004

Other (OTH) AF: 0.0592 AC: 125 AN: 2110

Alfa AF: 0.0402 Hom.: 281

Bravo AF: 0.0540

Asia WGS AF: 0.185 AC: 643 AN: 3478

EpiCase AF: 0.0169

EpiControl AF: 0.0164

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)
-	-	1	SHORT syndrome;C3554689:Agammaglobulinemia 7, autosomal recessive;C4014934:Immunodeficiency 36 with lymphoproliferation (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.25
CADD	Benign	13
DANN	Benign	0.76
PhyloP100		2.5
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3730090; hg19: chr5-67589188; COSMIC: COSV57123112; COSMIC: COSV57123112;