rs9903447

Variant names:

• chr17-8881770-A-C
• rs9903447
• NM_001142633.3:c.2299+18T>G

Variant summary

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

The NM_001142633.3(PIK3R5):​c.2299+18T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.25 in 1,612,248 control chromosomes in the GnomAD database, including 54,025 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.28 (6770 hom., cov: 31)
  • Exomes 𝑓: 0.25 (47255 hom.)
• Consequence: PIK3R5 NM_001142633.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.633
• Publications: 4 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

LOC124903919 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 17-8881770-A-C is Benign according to our data. Variant chr17-8881770-A-C is described in ClinVar as Benign. ClinVar VariationId is 257557.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.396 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIK3R5	NM_001142633.3	c.2299+18T>G		intron_variant	Intron 16 of 18	ENST00000447110.6	NP_001136105.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PIK3R5	ENST00000447110.6	c.2299+18T>G		intron_variant	Intron 16 of 18	5	NM_001142633.3	ENSP00000392812.1

Frequencies

GnomAD3 genomes AF: 0.281 AC: 42534 AN: 151490 Hom.: 6764 Cov.: 31

Gnomad AFR AF: 0.401

Gnomad AMI AF: 0.401

Gnomad AMR AF: 0.278

Gnomad ASJ AF: 0.301

Gnomad EAS AF: 0.00136

Gnomad SAS AF: 0.120

Gnomad FIN AF: 0.161

Gnomad MID AF: 0.259

Gnomad NFE AF: 0.257

Gnomad OTH AF: 0.270

GnomAD2 exomes AF: 0.222 AC: 55607 AN: 250724 AF XY: 0.215

Gnomad AFR exome AF: 0.407

Gnomad AMR exome AF: 0.228

Gnomad ASJ exome AF: 0.289

Gnomad EAS exome AF: 0.000653

Gnomad FIN exome AF: 0.163

Gnomad NFE exome AF: 0.260

Gnomad OTH exome AF: 0.246

GnomAD4 exome AF: 0.247 AC: 360117 AN: 1460640 Hom.: 47255 Cov.: 32 AF XY: 0.241 AC XY: 175485 AN XY: 726682

African (AFR) AF: 0.406 AC: 13579 AN: 33450

American (AMR) AF: 0.236 AC: 10544 AN: 44674

Ashkenazi Jewish (ASJ) AF: 0.285 AC: 7454 AN: 26128

East Asian (EAS) AF: 0.000428 AC: 17 AN: 39694

South Asian (SAS) AF: 0.127 AC: 10966 AN: 86218

European-Finnish (FIN) AF: 0.178 AC: 9492 AN: 53406

Middle Eastern (MID) AF: 0.203 AC: 1170 AN: 5766

European-Non Finnish (NFE) AF: 0.263 AC: 292221 AN: 1110952

Other (OTH) AF: 0.243 AC: 14674 AN: 60352

GnomAD4 genome AF: 0.281 AC: 42568 AN: 151608 Hom.: 6770 Cov.: 31 AF XY: 0.271 AC XY: 20036 AN XY: 74048

African (AFR) AF: 0.401 AC: 16540 AN: 41268

American (AMR) AF: 0.278 AC: 4242 AN: 15242

Ashkenazi Jewish (ASJ) AF: 0.301 AC: 1042 AN: 3464

East Asian (EAS) AF: 0.00136 AC: 7 AN: 5154

South Asian (SAS) AF: 0.119 AC: 569 AN: 4790

European-Finnish (FIN) AF: 0.161 AC: 1702 AN: 10548

Middle Eastern (MID) AF: 0.255 AC: 75 AN: 294

European-Non Finnish (NFE) AF: 0.257 AC: 17466 AN: 67842

Other (OTH) AF: 0.268 AC: 562 AN: 2100

Alfa AF: 0.264 Hom.: 1342

Bravo AF: 0.297

Asia WGS AF: 0.0800 AC: 281 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

-

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	-0.92
CADD	Benign	0.62
DANN	Benign	0.49
PhyloP100		-0.63
PromoterAI		0.053	Neutral
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: rs9903447; hg19: chr17-8785087; COSMIC: COSV52650696;