chr17-8888712-A-G

Variant names:

• chr17-8888712-A-G
• rs381309
• ENST00000623421.3:c.-84T>C

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.-84T>C 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 0.417 in 1,613,248 control chromosomes in the GnomAD database, including 144,661 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.47 (18296 hom., cov: 33)
  • Exomes 𝑓: 0.41 (126365 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: 0.372
• Publications: 23 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=-0.85).
• BP6: Variant 17-8888712-A-G is Benign according to our data. Variant chr17-8888712-A-G is described in ClinVar as Benign. ClinVar VariationId is 129893.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.658 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000623421.3. 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
	PIK3R5	NM_001142633.3	MANE Select	c.1075T>C	p.Leu359Leu	synonymous	Exon 10 of 19	NP_001136105.1
	PIK3R5	NM_001251851.2		c.-84T>C		5_prime_UTR_premature_start_codon_gain	Exon 10 of 19	NP_001238780.1
	PIK3R5	NM_001251852.2		c.-84T>C		5_prime_UTR_premature_start_codon_gain	Exon 9 of 18	NP_001238781.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIK3R5	ENST00000623421.3	TSL:1	c.-84T>C		5_prime_UTR_premature_start_codon_gain	Exon 9 of 18	ENSP00000485280.1
	PIK3R5	ENST00000447110.6	TSL:5 MANE Select	c.1075T>C	p.Leu359Leu	synonymous	Exon 10 of 19	ENSP00000392812.1
	PIK3R5	ENST00000581552.5	TSL:1	c.1075T>C	p.Leu359Leu	synonymous	Exon 10 of 19	ENSP00000462433.1

Frequencies

GnomAD3 genomes AF: 0.469 AC: 71342 AN: 152052 Hom.: 18247 Cov.: 33

Gnomad AFR AF: 0.664

Gnomad AMI AF: 0.511

Gnomad AMR AF: 0.440

Gnomad ASJ AF: 0.505

Gnomad EAS AF: 0.174

Gnomad SAS AF: 0.420

Gnomad FIN AF: 0.290

Gnomad MID AF: 0.541

Gnomad NFE AF: 0.408

Gnomad OTH AF: 0.471

GnomAD2 exomes AF: 0.402 AC: 99320 AN: 246878 AF XY: 0.399

Gnomad AFR exome AF: 0.674

Gnomad AMR exome AF: 0.387

Gnomad ASJ exome AF: 0.497

Gnomad EAS exome AF: 0.167

Gnomad FIN exome AF: 0.293

Gnomad NFE exome AF: 0.414

Gnomad OTH exome AF: 0.415

GnomAD4 exome AF: 0.411 AC: 600753 AN: 1461078 Hom.: 126365 Cov.: 50 AF XY: 0.410 AC XY: 298058 AN XY: 726806

African (AFR) AF: 0.675 AC: 22612 AN: 33476

American (AMR) AF: 0.395 AC: 17636 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.495 AC: 12928 AN: 26130

East Asian (EAS) AF: 0.193 AC: 7681 AN: 39698

South Asian (SAS) AF: 0.423 AC: 36445 AN: 86254

European-Finnish (FIN) AF: 0.304 AC: 16095 AN: 53006

Middle Eastern (MID) AF: 0.447 AC: 2577 AN: 5768

European-Non Finnish (NFE) AF: 0.413 AC: 459233 AN: 1111670

Other (OTH) AF: 0.423 AC: 25546 AN: 60376

GnomAD4 genome AF: 0.470 AC: 71448 AN: 152170 Hom.: 18296 Cov.: 33 AF XY: 0.459 AC XY: 34178 AN XY: 74406

African (AFR) AF: 0.665 AC: 27609 AN: 41538

American (AMR) AF: 0.441 AC: 6735 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.505 AC: 1753 AN: 3470

East Asian (EAS) AF: 0.174 AC: 902 AN: 5178

South Asian (SAS) AF: 0.418 AC: 2017 AN: 4822

European-Finnish (FIN) AF: 0.290 AC: 3080 AN: 10608

Middle Eastern (MID) AF: 0.545 AC: 159 AN: 292

European-Non Finnish (NFE) AF: 0.408 AC: 27736 AN: 67960

Other (OTH) AF: 0.471 AC: 993 AN: 2110

Alfa AF: 0.440 Hom.: 23788

Bravo AF: 0.487

Asia WGS AF: 0.301 AC: 1045 AN: 3478

EpiCase AF: 0.417

EpiControl AF: 0.420

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	7.0
DANN	Benign	0.56
PhyloP100		0.37
Mutation Taster		=100/0	polymorphism (auto)

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: rs381309; hg19: chr17-8792029; COSMIC: COSV52653919; COSMIC: COSV52653919;