5-68227023-A-T

Variant names:

• chr5-68227023-A-T
• rs706714
• NM_181523.3:c.334+14A>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_181523.3(PIK3R1):​c.334+14A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000007 in 1,427,564 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: PIK3R1 NM_181523.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.32
• Publications: 17 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIK3R1	NM_181523.3	c.334+14A>T		intron_variant	Intron 2 of 15	ENST00000521381.6	NP_852664.1
PIK3R1	XM_005248542.4	c.334+14A>T		intron_variant	Intron 2 of 15		XP_005248599.1
PIK3R1	XM_017009585.3	c.334+14A>T		intron_variant	Intron 2 of 15		XP_016865074.1
PIK3R1	XM_047417315.1	c.334+14A>T		intron_variant	Intron 2 of 15		XP_047273271.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PIK3R1	ENST00000521381.6	c.334+14A>T		intron_variant	Intron 2 of 15	1	NM_181523.3	ENSP00000428056.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.00e-7 AC: 1 AN: 1427564 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 708376

African (AFR) AF: 0.00 AC: 0 AN: 31566

American (AMR) AF: 0.00 AC: 0 AN: 37710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24306

East Asian (EAS) AF: 0.00 AC: 0 AN: 39316

South Asian (SAS) AF: 0.00 AC: 0 AN: 81914

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52266

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5574

European-Non Finnish (NFE) AF: 9.12e-7 AC: 1 AN: 1096116

Other (OTH) AF: 0.00 AC: 0 AN: 58796

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	12
DANN	Benign	0.71
PhyloP100		1.3

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: rs706714; hg19: chr5-67522851;