rs41268435

Variant names:

• chr5-68297604-C-T
• rs41268435
• NM_181523.3:c.*3C>T

Your query was ambiguous. Multiple possible variants found:

• chr5-68297604-C-T
• chr5-68297604-C-A
• chr5-68297604-C-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_181523.3(PIK3R1):​c.*3C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00959 in 1,612,452 control chromosomes in the GnomAD database, including 145 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0097 (16 hom., cov: 32)
  • Exomes 𝑓: 0.0096 (129 hom.)
• Consequence: PIK3R1 NM_181523.3 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.02
• 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: 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: ClinGen, Labcorp Genetics (formerly Invitae), Orphanet, G2P, Genomics England PanelApp, Ambry Genetics
• agammaglobulinemia 7, autosomal recessive

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P, 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 (BayesDel_noAF=-0.75).
• BP6: Variant 5-68297604-C-T is Benign according to our data. Variant chr5-68297604-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 211905.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00967 (1472/152272) while in subpopulation AMR AF = 0.00935 (143/15292). AF 95% confidence interval is 0.00822. There are 16 homozygotes in GnomAd4. There are 862 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 16 AD,AR gene

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.*3C>T		3_prime_UTR	Exon 16 of 16	NP_852664.1	A0A2X0SFG1
	PIK3R1	NM_181504.4		c.*3C>T		3_prime_UTR	Exon 10 of 10	NP_852556.2
	PIK3R1	NM_181524.2		c.*3C>T		3_prime_UTR	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.*3C>T		3_prime_UTR	Exon 16 of 16	ENSP00000428056.1	P27986-1
	PIK3R1	ENST00000336483.10	TSL:1	c.*3C>T		3_prime_UTR	Exon 10 of 10	ENSP00000338554.5	P27986-2
	PIK3R1	ENST00000320694.13	TSL:1	c.*3C>T		3_prime_UTR	Exon 10 of 10	ENSP00000323512.8	P27986-3

Frequencies

GnomAD3 genomes AF: 0.00969 AC: 1474 AN: 152154 Hom.: 16 Cov.: 32

Gnomad AFR AF: 0.00195

Gnomad AMI AF: 0.0154

Gnomad AMR AF: 0.00936

Gnomad ASJ AF: 0.0279

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00539

Gnomad FIN AF: 0.0454

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.00882

Gnomad OTH AF: 0.0120

GnomAD2 exomes AF: 0.0108 AC: 2701 AN: 249326 AF XY: 0.0114

Gnomad AFR exome AF: 0.00117

Gnomad AMR exome AF: 0.00496

Gnomad ASJ exome AF: 0.0299

Gnomad EAS exome AF: 0.0000545

Gnomad FIN exome AF: 0.0426

Gnomad NFE exome AF: 0.00919

Gnomad OTH exome AF: 0.0131

GnomAD4 exome AF: 0.00958 AC: 13995 AN: 1460180 Hom.: 129 Cov.: 30 AF XY: 0.00973 AC XY: 7071 AN XY: 726426

African (AFR) AF: 0.00233 AC: 78 AN: 33424

American (AMR) AF: 0.00550 AC: 245 AN: 44548

Ashkenazi Jewish (ASJ) AF: 0.0296 AC: 769 AN: 25998

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39668

South Asian (SAS) AF: 0.00637 AC: 548 AN: 86032

European-Finnish (FIN) AF: 0.0381 AC: 2035 AN: 53372

Middle Eastern (MID) AF: 0.0259 AC: 149 AN: 5744

European-Non Finnish (NFE) AF: 0.00859 AC: 9539 AN: 1111064

Other (OTH) AF: 0.0105 AC: 631 AN: 60330

GnomAD4 genome AF: 0.00967 AC: 1472 AN: 152272 Hom.: 16 Cov.: 32 AF XY: 0.0116 AC XY: 862 AN XY: 74446

African (AFR) AF: 0.00195 AC: 81 AN: 41560

American (AMR) AF: 0.00935 AC: 143 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0279 AC: 97 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00539 AC: 26 AN: 4820

European-Finnish (FIN) AF: 0.0454 AC: 481 AN: 10604

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.00881 AC: 599 AN: 68028

Other (OTH) AF: 0.0114 AC: 24 AN: 2110

Alfa AF: 0.00842 Hom.: 5

Bravo AF: 0.00700

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.0107

EpiControl AF: 0.0141

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)
-	-	1	PIK3R1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	10
DANN	Benign	0.87
PhyloP100		1.0
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs41268435;

hg19: chr5-67593432;

COSMIC: COSV99163910;