5-68226396-A-G

Variant names:

• chr5-68226396-A-G
• rs59576080
• ENST00000517412.2:n.321A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_181523.3(PIK3R1):​c.-280A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00578 in 476,310 control chromosomes in the GnomAD database, including 72 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.014 (54 hom., cov: 32)
  • Exomes 𝑓: 0.0019 (18 hom.)
• Consequence: PIK3R1 NM_181523.3 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.328
• Publications: 0 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 5-68226396-A-G is Benign according to our data. Variant chr5-68226396-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 1204979.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.014 (2131/152278) while in subpopulation AFR AF = 0.0491 (2038/41522). AF 95% confidence interval is 0.0473. There are 54 homozygotes in GnomAd4. There are 1012 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 54 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIK3R1	NM_181523.3	c.-280A>G		5_prime_UTR_variant	Exon 2 of 16	ENST00000521381.6	NP_852664.1
PIK3R1	XM_005248542.4	c.-280A>G		5_prime_UTR_variant	Exon 2 of 16		XP_005248599.1
PIK3R1	XM_017009585.3	c.-280A>G		5_prime_UTR_variant	Exon 2 of 16		XP_016865074.1
PIK3R1	XM_047417315.1	c.-280A>G		5_prime_UTR_variant	Exon 2 of 16		XP_047273271.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PIK3R1	ENST00000521381.6	c.-280A>G		5_prime_UTR_variant	Exon 2 of 16	1	NM_181523.3	ENSP00000428056.1

Frequencies

GnomAD3 genomes AF: 0.0140 AC: 2129 AN: 152160 Hom.: 54 Cov.: 32

Gnomad AFR AF: 0.0492

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00419

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.0100

GnomAD4 exome AF: 0.00192 AC: 622 AN: 324032 Hom.: 18 Cov.: 0 AF XY: 0.00159 AC XY: 264 AN XY: 166110

African (AFR) AF: 0.0481 AC: 507 AN: 10536

American (AMR) AF: 0.00238 AC: 30 AN: 12584

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 11094

East Asian (EAS) AF: 0.00 AC: 0 AN: 28218

South Asian (SAS) AF: 0.00 AC: 0 AN: 13810

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 22946

Middle Eastern (MID) AF: 0.000634 AC: 1 AN: 1578

European-Non Finnish (NFE) AF: 0.0000394 AC: 8 AN: 203020

Other (OTH) AF: 0.00375 AC: 76 AN: 20246

GnomAD4 genome AF: 0.0140 AC: 2131 AN: 152278 Hom.: 54 Cov.: 32 AF XY: 0.0136 AC XY: 1012 AN XY: 74478

African (AFR) AF: 0.0491 AC: 2038 AN: 41522

American (AMR) AF: 0.00418 AC: 64 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68030

Other (OTH) AF: 0.00994 AC: 21 AN: 2112

Alfa AF: 0.0103 Hom.: 3

Bravo AF: 0.0157

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jan 16, 2019

GeneDx

Significance: Likely 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	-0.80
CADD	Benign	5.4
DANN	Benign	0.85
PhyloP100		-0.33
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=300/0	polymorphism

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: rs59576080; hg19: chr5-67522224;