5-68273651-A-G

Variant names:

• chr5-68273651-A-G
• rs2302975
• ENST00000517412.2:n.1196A>G

Variant summary

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

The ENST00000517412.2(PIK3R1):​n.1196A>G variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.472 in 623,802 control chromosomes in the GnomAD database, including 73,154 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.54 (23799 hom., cov: 31)
  • Exomes 𝑓: 0.45 (49355 hom.)
• Consequence: PIK3R1 ENST00000517412.2 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.378
• Publications: 14 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 5-68273651-A-G is Benign according to our data. Variant chr5-68273651-A-G is described in ClinVar as Benign. ClinVar VariationId is 1226091.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.775 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000517412.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIK3R1	NM_181523.3	MANE Select	c.427+169A>G		intron	N/A	NP_852664.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIK3R1	ENST00000517412.2	TSL:1	n.1196A>G		non_coding_transcript_exon	Exon 3 of 3
	PIK3R1	ENST00000521381.6	TSL:1 MANE Select	c.427+169A>G		intron	N/A	ENSP00000428056.1
	PIK3R1	ENST00000697461.1		c.427+169A>G		intron	N/A	ENSP00000513319.1

Frequencies

GnomAD3 genomes AF: 0.537 AC: 81544 AN: 151848 Hom.: 23765 Cov.: 31

Gnomad AFR AF: 0.782

Gnomad AMI AF: 0.459

Gnomad AMR AF: 0.391

Gnomad ASJ AF: 0.460

Gnomad EAS AF: 0.408

Gnomad SAS AF: 0.496

Gnomad FIN AF: 0.469

Gnomad MID AF: 0.535

Gnomad NFE AF: 0.449

Gnomad OTH AF: 0.522

GnomAD4 exome AF: 0.451 AC: 212736 AN: 471836 Hom.: 49355 Cov.: 5 AF XY: 0.453 AC XY: 112976 AN XY: 249176

African (AFR) AF: 0.779 AC: 10089 AN: 12954

American (AMR) AF: 0.318 AC: 6311 AN: 19874

Ashkenazi Jewish (ASJ) AF: 0.451 AC: 6317 AN: 14002

East Asian (EAS) AF: 0.381 AC: 12217 AN: 32090

South Asian (SAS) AF: 0.490 AC: 21841 AN: 44530

European-Finnish (FIN) AF: 0.456 AC: 15407 AN: 33786

Middle Eastern (MID) AF: 0.504 AC: 1769 AN: 3510

European-Non Finnish (NFE) AF: 0.444 AC: 126067 AN: 284226

Other (OTH) AF: 0.473 AC: 12718 AN: 26864

GnomAD4 genome AF: 0.537 AC: 81623 AN: 151966 Hom.: 23799 Cov.: 31 AF XY: 0.535 AC XY: 39726 AN XY: 74262

African (AFR) AF: 0.782 AC: 32422 AN: 41460

American (AMR) AF: 0.391 AC: 5962 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.460 AC: 1593 AN: 3466

East Asian (EAS) AF: 0.407 AC: 2107 AN: 5174

South Asian (SAS) AF: 0.496 AC: 2387 AN: 4814

European-Finnish (FIN) AF: 0.469 AC: 4940 AN: 10534

Middle Eastern (MID) AF: 0.527 AC: 155 AN: 294

European-Non Finnish (NFE) AF: 0.450 AC: 30545 AN: 67952

Other (OTH) AF: 0.521 AC: 1093 AN: 2098

Alfa AF: 0.470 Hom.: 59937

Bravo AF: 0.538

Asia WGS AF: 0.520 AC: 1812 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Jun 26, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.5
DANN	Benign	0.46
PhyloP100		-0.38
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: rs2302975; hg19: chr5-67569479; COSMIC: COSV57139780;