rs16957702

Variant names:

• chr17-8888776-G-A
• rs16957702
• ENST00000623421.3:c.-148C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000623421.3(PIK3R5):​c.-148C>T variant causes a 5 prime UTR premature start codon gain 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 ENST00000623421.3 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -3.54
• Publications: 15 publications found

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]

PIK3R5 Gene-Disease associations (from GenCC):

• spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000297004 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 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 VariationId is 129892.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
PIK3R5	NM_001142633.3	c.1011C>T	p.Asp337Asp	synonymous_variant	Exon 10 of 19	ENST00000447110.6	NP_001136105.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PIK3R5	ENST00000447110.6	c.1011C>T	p.Asp337Asp	synonymous_variant	Exon 10 of 19	5	NM_001142633.3	ENSP00000392812.1

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

GnomAD2 exomes AF: 0.246 AC: 60115 AN: 243942 AF XY: 0.244

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 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

African (AFR) AF: 0.292 AC: 9758 AN: 33474

American (AMR) AF: 0.251 AC: 11199 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.320 AC: 8350 AN: 26128

East Asian (EAS) AF: 0.000655 AC: 26 AN: 39696

South Asian (SAS) AF: 0.165 AC: 14263 AN: 86238

European-Finnish (FIN) AF: 0.207 AC: 10796 AN: 52248

Middle Eastern (MID) AF: 0.250 AC: 1443 AN: 5768

European-Non Finnish (NFE) AF: 0.309 AC: 343318 AN: 1111472

Other (OTH) AF: 0.275 AC: 16620 AN: 60378

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

African (AFR) AF: 0.292 AC: 12147 AN: 41532

American (AMR) AF: 0.301 AC: 4609 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.332 AC: 1153 AN: 3472

East Asian (EAS) AF: 0.00212 AC: 11 AN: 5188

South Asian (SAS) AF: 0.154 AC: 745 AN: 4834

European-Finnish (FIN) AF: 0.189 AC: 2005 AN: 10614

Middle Eastern (MID) AF: 0.303 AC: 89 AN: 294

European-Non Finnish (NFE) AF: 0.303 AC: 20600 AN: 67964

Other (OTH) AF: 0.295 AC: 623 AN: 2110

Alfa AF: 0.294 Hom.: 6472

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:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

-

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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. -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Ataxia with oculomotor apraxia type 3 Benign:1

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.12
DANN	Benign	0.58
PhyloP100		-3.5
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs16957702; hg19: chr17-8792093; COSMIC: COSV52652198; COSMIC: COSV52652198;