rs16957702

chr17-8888776-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001142633.3(PIK3R5):c.1011C>T(p.Asp337=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.284 in 1,612,304 control chromosomes in the GnomAD database, including 68,661 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.28 (6332 hom., cov: 33)
  • Exomes 𝑓: 0.28 (62329 hom.)
• Consequence: PIK3R5 NM_001142633.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -3.54

Genes affected

PIK3R5 (HGNC:30035): (phosphoinositide-3-kinase regulatory subunit 5) Phosphatidylinositol 3-kinases (PI3Ks) phosphorylate the inositol ring of phosphatidylinositol at the 3-prime position, and play important roles in cell growth, proliferation, differentiation, motility, survival and intracellular trafficking. The PI3Ks are divided into three classes: I, II and III, and only the class I PI3Ks are involved in oncogenesis. This gene encodes the 101 kD regulatory subunit of the class I PI3K gamma complex, which is a dimeric enzyme, consisting of a 110 kD catalytic subunit gamma and a regulatory subunit of either 55, 87 or 101 kD. This protein recruits the catalytic subunit from the cytosol to the plasma membrane through high-affinity interaction with G-beta-gamma proteins. Multiple alternatively spliced transcript variants encoding two distinct isoforms have been found. [provided by RefSeq, Oct 2011]

LOC124903922 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 17-8888776-G-A is Benign according to our data. Variant chr17-8888776-G-A is described in ClinVar as [Benign]. Clinvar id is 129892.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-8888776-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-3.54 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.3 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PIK3R5	NM_001142633.3	c.1011C>T	p.Asp337=	synonymous_variant	10/19	ENST00000447110.6
LOC124903922	XR_007065613.1	n.79+1076G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PIK3R5	ENST00000447110.6	c.1011C>T	p.Asp337=	synonymous_variant	10/19	5	NM_001142633.3	P4

Frequencies

GnomAD3 genomes AF: 0.278 AC: 42341 AN: 152092 Hom.: 6315 Cov.: 33

Gnomad AFR AF: 0.292

Gnomad AMI AF: 0.453

Gnomad AMR AF: 0.301

Gnomad ASJ AF: 0.332

Gnomad EAS AF: 0.00212

Gnomad SAS AF: 0.156

Gnomad FIN AF: 0.189

Gnomad MID AF: 0.301

Gnomad NFE AF: 0.303

Gnomad OTH AF: 0.298

GnomAD3 exomes AF: 0.246 AC: 60115 AN: 243942 Hom.: 8554 AF XY: 0.244 AC XY: 32232 AN XY: 132238

Gnomad AFR exome AF: 0.295

Gnomad AMR exome AF: 0.243

Gnomad ASJ exome AF: 0.322

Gnomad EAS exome AF: 0.000708

Gnomad SAS exome AF: 0.162

Gnomad FIN exome AF: 0.191

Gnomad NFE exome AF: 0.308

Gnomad OTH exome AF: 0.278

GnomAD4 exome AF: 0.285 AC: 415773 AN: 1460094 Hom.: 62329 Cov.: 39 AF XY: 0.280 AC XY: 203326 AN XY: 726244

Gnomad4 AFR exome AF: 0.292

Gnomad4 AMR exome AF: 0.251

Gnomad4 ASJ exome AF: 0.320

Gnomad4 EAS exome AF: 0.000655

Gnomad4 SAS exome AF: 0.165

Gnomad4 FIN exome AF: 0.207

Gnomad4 NFE exome AF: 0.309

Gnomad4 OTH exome AF: 0.275

GnomAD4 genome AF: 0.279 AC: 42393 AN: 152210 Hom.: 6332 Cov.: 33 AF XY: 0.268 AC XY: 19955 AN XY: 74432

Gnomad4 AFR AF: 0.292

Gnomad4 AMR AF: 0.301

Gnomad4 ASJ AF: 0.332

Gnomad4 EAS AF: 0.00212

Gnomad4 SAS AF: 0.154

Gnomad4 FIN AF: 0.189

Gnomad4 NFE AF: 0.303

Gnomad4 OTH AF: 0.295

Alfa AF: 0.293 Hom.: 4730

Bravo AF: 0.288

Asia WGS AF: 0.0930 AC: 322 AN: 3478

EpiCase AF: 0.307

EpiControl AF: 0.310

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Ataxia with oculomotor apraxia type 3 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 05, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
Cadd	Benign	0.12
Dann	Benign	0.58

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs16957702; hg19: chr17-8792093; COSMIC: COSV52652198; COSMIC: COSV52652198;