rs3730089

Variant names:

• chr5-68292320-G-A
• rs3730089
• NM_181523.3:c.978G>A

Your query was ambiguous. Multiple possible variants found:

• chr5-68292320-G-A
• chr5-68292320-G-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_181523.3(PIK3R1):​c.978G>A​(p.Met326Ile) variant causes a missense change. The variant allele was found at a frequency of 0.171 in 1,610,794 control chromosomes in the GnomAD database, including 26,801 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.22 (4645 hom., cov: 32)
  • Exomes 𝑓: 0.17 (22156 hom.)
• Consequence: PIK3R1 NM_181523.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7 O:1
• Conservation: PhyloP100: 4.65
• Publications: 119 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0020537376).
• BP6: Variant 5-68292320-G-A is Benign according to our data. Variant chr5-68292320-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 135039.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.375 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.978G>A	p.Met326Ile	missense	Exon 8 of 16	NP_852664.1	A0A2X0SFG1
	PIK3R1	NM_181504.4		c.168G>A	p.Met56Ile	missense	Exon 2 of 10	NP_852556.2
	PIK3R1	NM_181524.2		c.78G>A	p.Met26Ile	missense	Exon 2 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.978G>A	p.Met326Ile	missense	Exon 8 of 16	ENSP00000428056.1	P27986-1
	PIK3R1	ENST00000336483.10	TSL:1	c.168G>A	p.Met56Ile	missense	Exon 2 of 10	ENSP00000338554.5	P27986-2
	PIK3R1	ENST00000320694.13	TSL:1	c.78G>A	p.Met26Ile	missense	Exon 2 of 10	ENSP00000323512.8	P27986-3

Frequencies

GnomAD3 genomes AF: 0.219 AC: 33242 AN: 151966 Hom.: 4637 Cov.: 32

Gnomad AFR AF: 0.380

Gnomad AMI AF: 0.141

Gnomad AMR AF: 0.224

Gnomad ASJ AF: 0.170

Gnomad EAS AF: 0.173

Gnomad SAS AF: 0.0759

Gnomad FIN AF: 0.126

Gnomad MID AF: 0.152

Gnomad NFE AF: 0.152

Gnomad OTH AF: 0.187

GnomAD2 exomes AF: 0.178 AC: 44681 AN: 251082 AF XY: 0.166

Gnomad AFR exome AF: 0.384

Gnomad AMR exome AF: 0.286

Gnomad ASJ exome AF: 0.170

Gnomad EAS exome AF: 0.175

Gnomad FIN exome AF: 0.129

Gnomad NFE exome AF: 0.155

Gnomad OTH exome AF: 0.150

GnomAD4 exome AF: 0.166 AC: 242830 AN: 1458710 Hom.: 22156 Cov.: 30 AF XY: 0.161 AC XY: 117149 AN XY: 725892

African (AFR) AF: 0.389 AC: 12978 AN: 33346

American (AMR) AF: 0.279 AC: 12456 AN: 44600

Ashkenazi Jewish (ASJ) AF: 0.167 AC: 4352 AN: 26102

East Asian (EAS) AF: 0.162 AC: 6422 AN: 39674

South Asian (SAS) AF: 0.0800 AC: 6890 AN: 86176

European-Finnish (FIN) AF: 0.125 AC: 6696 AN: 53366

Middle Eastern (MID) AF: 0.138 AC: 794 AN: 5756

European-Non Finnish (NFE) AF: 0.164 AC: 182036 AN: 1109384

Other (OTH) AF: 0.169 AC: 10206 AN: 60306

GnomAD4 genome AF: 0.219 AC: 33291 AN: 152084 Hom.: 4645 Cov.: 32 AF XY: 0.216 AC XY: 16046 AN XY: 74330

African (AFR) AF: 0.380 AC: 15748 AN: 41460

American (AMR) AF: 0.225 AC: 3436 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.170 AC: 588 AN: 3468

East Asian (EAS) AF: 0.174 AC: 901 AN: 5184

South Asian (SAS) AF: 0.0760 AC: 366 AN: 4818

European-Finnish (FIN) AF: 0.126 AC: 1333 AN: 10570

Middle Eastern (MID) AF: 0.167 AC: 49 AN: 294

European-Non Finnish (NFE) AF: 0.152 AC: 10348 AN: 67988

Other (OTH) AF: 0.186 AC: 393 AN: 2112

Alfa AF: 0.174 Hom.: 12120

Bravo AF: 0.241

TwinsUK AF: 0.176 AC: 651

ALSPAC AF: 0.168 AC: 649

ESP6500AA AF: 0.382 AC: 1684

ESP6500EA AF: 0.165 AC: 1415

ExAC AF: 0.174 AC: 21145

Asia WGS AF: 0.121 AC: 420 AN: 3478

EpiCase AF: 0.153

EpiControl AF: 0.158

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (4)
-	-	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
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	22
DANN	Benign	0.95
DEOGEN2	Benign	0.33	T
Eigen	Benign	-0.12
Eigen_PC	Benign	0.050
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.64	T
MetaRNN	Benign	0.0021	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N
PhyloP100		4.6
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	-0.44	N
REVEL	Benign	0.086
Sift	Benign	0.45	T
Sift4G	Benign	0.22	T
Polyphen		0.0	B
Vest4		0.12
MutPred		0.14		Loss of disorder (P = 0.0549)
MPC		1.2
ClinPred		0.013	T
GERP RS		4.3
PromoterAI		-0.072	Neutral
Varity_R		0.40
gMVP		0.55
Mutation Taster		=85/15	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: rs3730089; hg19: chr5-67588148; COSMIC: COSV57127731; COSMIC: COSV57127731;