rs34175949

Positions:

• chr5-68280580-G-A
• chr5-68280580-G-C
• chr5-68280580-G-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_181523.3(PIK3R1):​c.687G>A​(p.Ser229Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00164 in 1,612,370 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0017 (4 hom.)
• Consequence: PIK3R1 NM_181523.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.660

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]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.4).
• BP6: Variant 5-68280580-G-A is Benign according to our data. Variant chr5-68280580-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 463167.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-68280580-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.66 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00139 (211/151574) while in subpopulation AMR AF= 0.00236 (36/15230). AF 95% confidence interval is 0.00176. There are 0 homozygotes in gnomad4. There are 97 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PIK3R1	NM_181523.3	c.687G>A	p.Ser229Ser	synonymous_variant	6/16	ENST00000521381.6	NP_852664.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PIK3R1	ENST00000521381.6	c.687G>A	p.Ser229Ser	synonymous_variant	6/16	1	NM_181523.3	ENSP00000428056.1

Frequencies

GnomAD3 genomes AF: 0.00140 AC: 212 AN: 151458 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000146

Gnomad AMI AF: 0.00771

Gnomad AMR AF: 0.00237

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00209

Gnomad FIN AF: 0.00259

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00172

Gnomad OTH AF: 0.00240

GnomAD3 exomes AF: 0.00171 AC: 429 AN: 251178 Hom.: 0 AF XY: 0.00180 AC XY: 245 AN XY: 135790

Gnomad AFR exome AF: 0.000247

Gnomad AMR exome AF: 0.00101

Gnomad ASJ exome AF: 0.000596

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00219

Gnomad FIN exome AF: 0.00231

Gnomad NFE exome AF: 0.00228

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.00167 AC: 2437 AN: 1460796 Hom.: 4 Cov.: 31 AF XY: 0.00172 AC XY: 1252 AN XY: 726760

Gnomad4 AFR exome AF: 0.000239

Gnomad4 AMR exome AF: 0.00130

Gnomad4 ASJ exome AF: 0.000804

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00198

Gnomad4 FIN exome AF: 0.00249

Gnomad4 NFE exome AF: 0.00173

Gnomad4 OTH exome AF: 0.00194

GnomAD4 genome AF: 0.00139 AC: 211 AN: 151574 Hom.: 0 Cov.: 32 AF XY: 0.00131 AC XY: 97 AN XY: 73992

Gnomad4 AFR AF: 0.000145

Gnomad4 AMR AF: 0.00236

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00188

Gnomad4 FIN AF: 0.00259

Gnomad4 NFE AF: 0.00172

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00137 Hom.: 0

Bravo AF: 0.00157

EpiCase AF: 0.00196

EpiControl AF: 0.00196

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jan 04, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	PIK3R1: BP4, BP7 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

SHORT syndrome;C3554689:Agammaglobulinemia 7, autosomal recessive;C4014934:Immunodeficiency 36 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 20, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.40
CADD	Benign	5.3
DANN	Benign	0.73

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

Publications

LitVar

Other links and lift over

dbSNP: rs34175949; hg19: chr5-67576408; COSMIC: COSV99140685;