chr5-68295256-TGACAAACGTATGAACAGC-T

Variant names:

• chr5-68295256-TGACAAACGTATGAACAGC-T
• rs1057519840
• NM_181523.3:c.1678_1695delGACAAACGTATGAACAGC

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1 PM4 PP3

The NM_181523.3(PIK3R1):​c.1678_1695delGACAAACGTATGAACAGC​(p.Asp560_Ser565del) variant causes a conservative inframe deletion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PIK3R1 NM_181523.3 conservative_inframe_deletion
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 10.0
• 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: Uncertain_significance. The variant received 5 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_181523.3
• PM4: Nonframeshift variant in NON repetitive region in NM_181523.3.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIK3R1	NM_181523.3	MANE Select	c.1678_1695delGACAAACGTATGAACAGC	p.Asp560_Ser565del	conservative_inframe_deletion	Exon 13 of 16	NP_852664.1
	PIK3R1	NM_181504.4		c.868_885delGACAAACGTATGAACAGC	p.Asp290_Ser295del	conservative_inframe_deletion	Exon 7 of 10	NP_852556.2
	PIK3R1	NM_181524.2		c.778_795delGACAAACGTATGAACAGC	p.Asp260_Ser265del	conservative_inframe_deletion	Exon 7 of 10	NP_852665.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIK3R1	ENST00000521381.6	TSL:1 MANE Select	c.1678_1695delGACAAACGTATGAACAGC	p.Asp560_Ser565del	conservative_inframe_deletion	Exon 13 of 16	ENSP00000428056.1
	PIK3R1	ENST00000336483.10	TSL:1	c.868_885delGACAAACGTATGAACAGC	p.Asp290_Ser295del	conservative_inframe_deletion	Exon 7 of 10	ENSP00000338554.5
	PIK3R1	ENST00000320694.13	TSL:1	c.778_795delGACAAACGTATGAACAGC	p.Asp260_Ser265del	conservative_inframe_deletion	Exon 7 of 10	ENSP00000323512.8

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		10

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1057519840; hg19: chr5-67591084;