rs61749601

Variant names:

• chr5-68279720-T-C
• rs61749601
• NM_181523.3:c.621T>C

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_181523.3(PIK3R1):​c.621T>C​(p.Ile207Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0353 in 1,613,960 control chromosomes in the GnomAD database, including 1,199 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.029 (98 hom., cov: 32)
  • Exomes 𝑓: 0.036 (1101 hom.)
• Consequence: PIK3R1 NM_181523.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.795
• Publications: 10 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: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 5-68279720-T-C is Benign according to our data. Variant chr5-68279720-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 159724.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.795 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.029 (4413/152310) while in subpopulation SAS AF = 0.0504 (243/4824). AF 95% confidence interval is 0.0452. There are 98 homozygotes in GnomAd4. There are 2183 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 98 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIK3R1	NM_181523.3	c.621T>C	p.Ile207Ile	synonymous_variant	Exon 5 of 16	ENST00000521381.6	NP_852664.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PIK3R1	ENST00000521381.6	c.621T>C	p.Ile207Ile	synonymous_variant	Exon 5 of 16	1	NM_181523.3	ENSP00000428056.1

Frequencies

GnomAD3 genomes AF: 0.0290 AC: 4414 AN: 152190 Hom.: 98 Cov.: 32

Gnomad AFR AF: 0.00584

Gnomad AMI AF: 0.0395

Gnomad AMR AF: 0.0240

Gnomad ASJ AF: 0.0450

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0505

Gnomad FIN AF: 0.0557

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.0397

Gnomad OTH AF: 0.0287

GnomAD2 exomes AF: 0.0352 AC: 8835 AN: 251160 AF XY: 0.0375

Gnomad AFR exome AF: 0.00554

Gnomad AMR exome AF: 0.0183

Gnomad ASJ exome AF: 0.0474

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0630

Gnomad NFE exome AF: 0.0401

Gnomad OTH exome AF: 0.0385

GnomAD4 exome AF: 0.0360 AC: 52561 AN: 1461650 Hom.: 1101 Cov.: 32 AF XY: 0.0371 AC XY: 26974 AN XY: 727152

African (AFR) AF: 0.00499 AC: 167 AN: 33474

American (AMR) AF: 0.0190 AC: 848 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.0447 AC: 1168 AN: 26130

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39700

South Asian (SAS) AF: 0.0496 AC: 4278 AN: 86238

European-Finnish (FIN) AF: 0.0633 AC: 3379 AN: 53416

Middle Eastern (MID) AF: 0.0428 AC: 247 AN: 5766

European-Non Finnish (NFE) AF: 0.0364 AC: 40432 AN: 1111818

Other (OTH) AF: 0.0337 AC: 2037 AN: 60390

GnomAD4 genome AF: 0.0290 AC: 4413 AN: 152310 Hom.: 98 Cov.: 32 AF XY: 0.0293 AC XY: 2183 AN XY: 74472

African (AFR) AF: 0.00582 AC: 242 AN: 41572

American (AMR) AF: 0.0239 AC: 366 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0450 AC: 156 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5178

South Asian (SAS) AF: 0.0504 AC: 243 AN: 4824

European-Finnish (FIN) AF: 0.0557 AC: 591 AN: 10612

Middle Eastern (MID) AF: 0.0510 AC: 15 AN: 294

European-Non Finnish (NFE) AF: 0.0397 AC: 2703 AN: 68034

Other (OTH) AF: 0.0284 AC: 60 AN: 2116

Alfa AF: 0.0353 Hom.: 80

Bravo AF: 0.0249

Asia WGS AF: 0.0170 AC: 59 AN: 3478

EpiCase AF: 0.0400

EpiControl AF: 0.0422

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 29, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 03, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:2

Oct 31, 2013

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

SHORT syndrome;C3554689:Agammaglobulinemia 7, autosomal recessive;C4014934:Immunodeficiency 36 with lymphoproliferation Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	9.7
DANN	Benign	0.73
PhyloP100		0.80
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: rs61749601; hg19: chr5-67575548; COSMIC: COSV57128723; COSMIC: COSV57128723;