chr5-68296465-A-C

Variant names:

• chr5-68296465-A-C
• rs3730073
• NM_181523.3:c.1985+124A>C

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.1985+124A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0232 in 878,750 control chromosomes in the GnomAD database, including 382 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.021 (57 hom., cov: 32)
  • Exomes 𝑓: 0.024 (325 hom.)
• Consequence: PIK3R1 NM_181523.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.163
• Publications: 2 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=-0.87).
• BP6: Variant 5-68296465-A-C is Benign according to our data. Variant chr5-68296465-A-C is described in ClinVar as Benign. ClinVar VariationId is 1247789.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.021 (3203/152316) while in subpopulation NFE AF = 0.0252 (1716/68032). AF 95% confidence interval is 0.0242. There are 57 homozygotes in GnomAd4. There are 1714 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 57 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIK3R1	NM_181523.3	MANE Select	c.1985+124A>C		intron	N/A	NP_852664.1
	PIK3R1	NM_181504.4		c.1175+124A>C		intron	N/A	NP_852556.2
	PIK3R1	NM_181524.2		c.1085+124A>C		intron	N/A	NP_852665.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIK3R1	ENST00000521381.6	TSL:1 MANE Select	c.1985+124A>C		intron	N/A	ENSP00000428056.1
	PIK3R1	ENST00000336483.10	TSL:1	c.1175+124A>C		intron	N/A	ENSP00000338554.5
	PIK3R1	ENST00000320694.13	TSL:1	c.1085+124A>C		intron	N/A	ENSP00000323512.8

Frequencies

GnomAD3 genomes AF: 0.0211 AC: 3204 AN: 152198 Hom.: 57 Cov.: 32

Gnomad AFR AF: 0.00470

Gnomad AMI AF: 0.0186

Gnomad AMR AF: 0.0223

Gnomad ASJ AF: 0.0545

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00807

Gnomad FIN AF: 0.0602

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0252

Gnomad OTH AF: 0.0254

GnomAD4 exome AF: 0.0237 AC: 17195 AN: 726434 Hom.: 325 AF XY: 0.0234 AC XY: 8700 AN XY: 371484

African (AFR) AF: 0.00387 AC: 70 AN: 18070

American (AMR) AF: 0.0167 AC: 361 AN: 21568

Ashkenazi Jewish (ASJ) AF: 0.0512 AC: 793 AN: 15490

East Asian (EAS) AF: 0.0000580 AC: 2 AN: 34472

South Asian (SAS) AF: 0.0108 AC: 555 AN: 51334

European-Finnish (FIN) AF: 0.0497 AC: 2073 AN: 41684

Middle Eastern (MID) AF: 0.0525 AC: 160 AN: 3046

European-Non Finnish (NFE) AF: 0.0245 AC: 12368 AN: 505648

Other (OTH) AF: 0.0231 AC: 813 AN: 35122

GnomAD4 genome AF: 0.0210 AC: 3203 AN: 152316 Hom.: 57 Cov.: 32 AF XY: 0.0230 AC XY: 1714 AN XY: 74478

African (AFR) AF: 0.00469 AC: 195 AN: 41582

American (AMR) AF: 0.0222 AC: 340 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0545 AC: 189 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00808 AC: 39 AN: 4826

European-Finnish (FIN) AF: 0.0602 AC: 639 AN: 10606

Middle Eastern (MID) AF: 0.0510 AC: 15 AN: 294

European-Non Finnish (NFE) AF: 0.0252 AC: 1716 AN: 68032

Other (OTH) AF: 0.0251 AC: 53 AN: 2110

Alfa AF: 0.00982 Hom.: 4

Bravo AF: 0.0175

Asia WGS AF: 0.00289 AC: 10 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.076
DANN	Benign	0.52
PhyloP100		-0.16
Mutation Taster		=100/0	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: rs3730073; hg19: chr5-67592293;