rs62620227

Positions:

chr17-8880725-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_001142633.3(PIK3R5):c.2557C>T(p.Pro853Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00345 in 1,613,940 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0027 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0035 ( 16 hom. )

Consequence

PIK3R5
NM_001142633.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5

Conservation

PhyloP100: -0.833

Variant links:

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 links:

LOC124903919 (HGNC:):

LOC124903919 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0077055395).

BP6

Variant 17-8880725-G-A is Benign according to our data. Variant chr17-8880725-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 211906.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=3}. Variant chr17-8880725-G-A is described in Lovd as [Likely_benign].

BS2

High Homozygotes in GnomAdExome4 at 16 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PIK3R5	NM_001142633.3 linkuse as main transcript	c.2557C>T	p.Pro853Ser	missense_variant	19/19	ENST00000447110.6
LOC124903919	XR_007065610.1 linkuse as main transcript	n.923+2421G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PIK3R5	ENST00000447110.6 linkuse as main transcript	c.2557C>T	p.Pro853Ser	missense_variant	19/19	5	NM_001142633.3	P4	Q8WYR1-1

Frequencies

GnomAD3 genomes

AF:

0.00275

AC:

418

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00327

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00248

Gnomad FIN

AF:

0.00508

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00370

Gnomad OTH

AF:

0.00383

GnomAD3 exomes

AF:

0.00297

AC:

741

AN:

249854

Hom.:

AF XY:

0.00308

AC XY:

416

AN XY:

135120

show subpopulations

Gnomad AFR exome

AF:

0.000616

Gnomad AMR exome

AF:

0.00281

Gnomad ASJ exome

AF:

0.00109

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00193

Gnomad FIN exome

AF:

0.00456

Gnomad NFE exome

AF:

0.00407

Gnomad OTH exome

AF:

0.00131

GnomAD4 exome

AF:

0.00352

AC:

5144

AN:

1461636

Hom.:

Cov.:

AF XY:

0.00353

AC XY:

2568

AN XY:

727106

show subpopulations

Gnomad4 AFR exome

AF:

0.000657

Gnomad4 AMR exome

AF:

0.00291

Gnomad4 ASJ exome

AF:

0.000995

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00194

Gnomad4 FIN exome

AF:

0.00348

Gnomad4 NFE exome

AF:

0.00399

Gnomad4 OTH exome

AF:

0.00300

GnomAD4 genome

AF:

0.00274

AC:

418

AN:

152304

Hom.:

Cov.:

AF XY:

0.00306

AC XY:

228

AN XY:

74478

show subpopulations

Gnomad4 AFR

AF:

0.000963

Gnomad4 AMR

AF:

0.00327

Gnomad4 ASJ

AF:

0.000576

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00248

Gnomad4 FIN

AF:

0.00508

Gnomad4 NFE

AF:

0.00370

Gnomad4 OTH

AF:

0.00379

Alfa

AF:

0.00335

Hom.:

Bravo

AF:

0.00252

TwinsUK

AF:

0.00351

AC:

ALSPAC

AF:

0.00311

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00488

AC:

ExAC

AF:

0.00280

AC:

340

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00365

EpiControl

AF:

0.00421

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:4

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jul 06, 2018	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	PIK3R5: BP4, BS2 -

Ataxia with oculomotor apraxia type 3

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Feb 26, 2018

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jul 03, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.058

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.47

CADD

Benign

0.028

DANN

Benign

0.38

DEOGEN2

Benign

0.11

T;.;.;.;T;.

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.43

T;.;.;T;.;T

M_CAP

Benign

0.033

MetaRNN

Benign

0.0077

T;T;T;T;T;T

MetaSVM

Benign

-0.85

MutationAssessor

Benign

0.18

N;.;.;.;N;.

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.27

PROVEAN

Benign

0.71

N;.;.;.;.;.

REVEL

Benign

0.10

Sift

Benign

0.50

T;.;.;.;.;.

Sift4G

Benign

0.45

T;T;T;T;T;T

Polyphen

0.0

B;.;.;.;B;.

Vest4

0.029

MVP

0.18

MPC

0.48

ClinPred

0.00090

GERP RS

-5.6

Varity_R

0.017

gMVP

0.16

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over