rs11650737

Variant names:

• chr17-8888854-T-C
• rs11650737
• ENST00000623421.3:c.-226A>G

Variant summary

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

The NM_001251851.2(PIK3R5):​c.-226A>G 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 0.285 in 1,604,864 control chromosomes in the GnomAD database, including 68,575 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.28 (6344 hom., cov: 33)
  • Exomes 𝑓: 0.29 (62231 hom.)
• Consequence: PIK3R5 NM_001251851.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.786
• Publications: 11 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=-0.72).
• BP6: Variant 17-8888854-T-C is Benign according to our data. Variant chr17-8888854-T-C is described in ClinVar as Benign. ClinVar VariationId is 129895.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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001251851.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIK3R5	NM_001142633.3	MANE Select	c.933A>G	p.Leu311Leu	synonymous	Exon 10 of 19	NP_001136105.1
	PIK3R5	NM_001251851.2		c.-226A>G		5_prime_UTR_premature_start_codon_gain	Exon 10 of 19	NP_001238780.1
	PIK3R5	NM_001251852.2		c.-226A>G		5_prime_UTR_premature_start_codon_gain	Exon 9 of 18	NP_001238781.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIK3R5	ENST00000623421.3	TSL:1	c.-226A>G		5_prime_UTR_premature_start_codon_gain	Exon 9 of 18	ENSP00000485280.1
	PIK3R5	ENST00000447110.6	TSL:5 MANE Select	c.933A>G	p.Leu311Leu	synonymous	Exon 10 of 19	ENSP00000392812.1
	PIK3R5	ENST00000581552.5	TSL:1	c.933A>G	p.Leu311Leu	synonymous	Exon 10 of 19	ENSP00000462433.1

Frequencies

GnomAD3 genomes AF: 0.279 AC: 42375 AN: 151962 Hom.: 6327 Cov.: 33

Gnomad AFR AF: 0.293

Gnomad AMI AF: 0.453

Gnomad AMR AF: 0.301

Gnomad ASJ AF: 0.332

Gnomad EAS AF: 0.00212

Gnomad SAS AF: 0.155

Gnomad FIN AF: 0.189

Gnomad MID AF: 0.301

Gnomad NFE AF: 0.304

Gnomad OTH AF: 0.299

GnomAD2 exomes AF: 0.248 AC: 59355 AN: 239436 AF XY: 0.245

Gnomad AFR exome AF: 0.296

Gnomad AMR exome AF: 0.243

Gnomad ASJ exome AF: 0.322

Gnomad EAS exome AF: 0.000713

Gnomad FIN exome AF: 0.192

Gnomad NFE exome AF: 0.307

Gnomad OTH exome AF: 0.278

GnomAD4 exome AF: 0.285 AC: 414544 AN: 1452784 Hom.: 62231 Cov.: 38 AF XY: 0.281 AC XY: 202809 AN XY: 722874

African (AFR) AF: 0.292 AC: 9759 AN: 33466

American (AMR) AF: 0.251 AC: 11215 AN: 44680

Ashkenazi Jewish (ASJ) AF: 0.320 AC: 8337 AN: 26092

East Asian (EAS) AF: 0.000630 AC: 25 AN: 39678

South Asian (SAS) AF: 0.165 AC: 14256 AN: 86212

European-Finnish (FIN) AF: 0.207 AC: 9369 AN: 45194

Middle Eastern (MID) AF: 0.250 AC: 1443 AN: 5766

European-Non Finnish (NFE) AF: 0.309 AC: 343542 AN: 1111398

Other (OTH) AF: 0.275 AC: 16598 AN: 60298

GnomAD4 genome AF: 0.279 AC: 42427 AN: 152080 Hom.: 6344 Cov.: 33 AF XY: 0.269 AC XY: 19969 AN XY: 74362

African (AFR) AF: 0.293 AC: 12156 AN: 41484

American (AMR) AF: 0.302 AC: 4614 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.332 AC: 1153 AN: 3468

East Asian (EAS) AF: 0.00213 AC: 11 AN: 5172

South Asian (SAS) AF: 0.154 AC: 744 AN: 4832

European-Finnish (FIN) AF: 0.189 AC: 2004 AN: 10586

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

European-Non Finnish (NFE) AF: 0.304 AC: 20619 AN: 67932

Other (OTH) AF: 0.296 AC: 625 AN: 2112

Alfa AF: 0.291 Hom.: 1383

Bravo AF: 0.289

Asia WGS AF: 0.0920 AC: 321 AN: 3478

EpiCase AF: 0.307

EpiControl AF: 0.310

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	1	Ataxia with oculomotor apraxia type 3 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	8.0
DANN	Benign	0.73
PhyloP100		0.79
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: rs11650737; hg19: chr17-8792171; COSMIC: COSV52653686; COSMIC: COSV52653686;