chr5-68297535-T-C

Variant names:

• chr5-68297535-T-C
• rs3729981
• NM_181523.3:c.2109T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_181523.3(PIK3R1):​c.2109T>C​(p.Leu703Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00882 in 1,614,152 control chromosomes in the GnomAD database, including 931 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.043 (466 hom., cov: 32)
  • Exomes 𝑓: 0.0052 (465 hom.)
• Consequence: PIK3R1 NM_181523.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.966
• Publications: 9 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).
• BP6: Variant 5-68297535-T-C is Benign according to our data. Variant chr5-68297535-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 159721.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.966 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.143 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.2109T>C	p.Leu703Leu	synonymous	Exon 16 of 16	NP_852664.1	A0A2X0SFG1
	PIK3R1	NM_181504.4		c.1299T>C	p.Leu433Leu	synonymous	Exon 10 of 10	NP_852556.2
	PIK3R1	NM_181524.2		c.1209T>C	p.Leu403Leu	synonymous	Exon 10 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.2109T>C	p.Leu703Leu	synonymous	Exon 16 of 16	ENSP00000428056.1	P27986-1
	PIK3R1	ENST00000336483.10	TSL:1	c.1299T>C	p.Leu433Leu	synonymous	Exon 10 of 10	ENSP00000338554.5	P27986-2
	PIK3R1	ENST00000320694.13	TSL:1	c.1209T>C	p.Leu403Leu	synonymous	Exon 10 of 10	ENSP00000323512.8	P27986-3

Frequencies

GnomAD3 genomes AF: 0.0432 AC: 6571 AN: 152174 Hom.: 463 Cov.: 32

Gnomad AFR AF: 0.146

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0238

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.00101

Gnomad OTH AF: 0.0407

GnomAD2 exomes AF: 0.0119 AC: 2981 AN: 251428 AF XY: 0.00875

Gnomad AFR exome AF: 0.150

Gnomad AMR exome AF: 0.00992

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.00112

Gnomad OTH exome AF: 0.00847

GnomAD4 exome AF: 0.00523 AC: 7649 AN: 1461860 Hom.: 465 Cov.: 31 AF XY: 0.00462 AC XY: 3362 AN XY: 727238

African (AFR) AF: 0.155 AC: 5204 AN: 33468

American (AMR) AF: 0.0116 AC: 520 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.000556 AC: 48 AN: 86258

European-Finnish (FIN) AF: 0.0000374 AC: 2 AN: 53414

Middle Eastern (MID) AF: 0.0198 AC: 114 AN: 5768

European-Non Finnish (NFE) AF: 0.000976 AC: 1085 AN: 1111996

Other (OTH) AF: 0.0112 AC: 674 AN: 60396

GnomAD4 genome AF: 0.0433 AC: 6592 AN: 152292 Hom.: 466 Cov.: 32 AF XY: 0.0415 AC XY: 3092 AN XY: 74484

African (AFR) AF: 0.146 AC: 6062 AN: 41534

American (AMR) AF: 0.0238 AC: 364 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.00101 AC: 69 AN: 68026

Other (OTH) AF: 0.0402 AC: 85 AN: 2112

Alfa AF: 0.0394 Hom.: 267

Bravo AF: 0.0486

Asia WGS AF: 0.0130 AC: 45 AN: 3478

EpiCase AF: 0.00136

EpiControl AF: 0.00148

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	-0.63
CADD	Benign	2.0
DANN	Benign	0.70
PhyloP100		-0.97
Mutation Taster		=96/4	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: rs3729981; hg19: chr5-67593363; COSMIC: COSV57135623; COSMIC: COSV57135623;