chr17-8881044-A-G

Variant names:

• chr17-8881044-A-G
• rs4791765
• NM_001142633.3:c.2383-27T>C

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.2383-27T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.301 in 1,561,406 control chromosomes in the GnomAD database, including 74,564 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.31 (7687 hom., cov: 32)
  • Exomes 𝑓: 0.30 (66877 hom.)
• Consequence: PIK3R5 NM_001142633.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.05
• Publications: 10 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
• ataxia with oculomotor apraxia type 3

  Inheritance: AR Classification: NO_KNOWN Submitted by: ClinGen

LOC124903919 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 17-8881044-A-G is Benign according to our data. Variant chr17-8881044-A-G is described in ClinVar as Benign. ClinVar VariationId is 1327033.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.344 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001142633.3. 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.2383-27T>C		intron	N/A	NP_001136105.1	L7RT34
	PIK3R5	NM_014308.4		c.2383-27T>C		intron	N/A	NP_055123.2	Q8WYR1-1
	PIK3R5	NM_001388396.1		c.2380-27T>C		intron	N/A	NP_001375325.1	J3KSW1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIK3R5	ENST00000447110.6	TSL:5 MANE Select	c.2383-27T>C		intron	N/A	ENSP00000392812.1	Q8WYR1-1
	PIK3R5	ENST00000581552.5	TSL:1	c.2383-27T>C		intron	N/A	ENSP00000462433.1	Q8WYR1-1
	PIK3R5	ENST00000623421.3	TSL:1	c.1225-27T>C		intron	N/A	ENSP00000485280.1	Q8WYR1-2

Frequencies

GnomAD3 genomes AF: 0.308 AC: 46710 AN: 151860 Hom.: 7665 Cov.: 32

Gnomad AFR AF: 0.348

Gnomad AMI AF: 0.460

Gnomad AMR AF: 0.317

Gnomad ASJ AF: 0.359

Gnomad EAS AF: 0.00251

Gnomad SAS AF: 0.158

Gnomad FIN AF: 0.237

Gnomad MID AF: 0.332

Gnomad NFE AF: 0.321

Gnomad OTH AF: 0.313

GnomAD2 exomes AF: 0.266 AC: 66590 AN: 250588 AF XY: 0.261

Gnomad AFR exome AF: 0.356

Gnomad AMR exome AF: 0.254

Gnomad ASJ exome AF: 0.348

Gnomad EAS exome AF: 0.000816

Gnomad FIN exome AF: 0.240

Gnomad NFE exome AF: 0.323

Gnomad OTH exome AF: 0.299

GnomAD4 exome AF: 0.300 AC: 422890 AN: 1409428 Hom.: 66877 Cov.: 24 AF XY: 0.295 AC XY: 207950 AN XY: 704186

African (AFR) AF: 0.353 AC: 11455 AN: 32426

American (AMR) AF: 0.261 AC: 11672 AN: 44642

Ashkenazi Jewish (ASJ) AF: 0.344 AC: 8896 AN: 25828

East Asian (EAS) AF: 0.000685 AC: 27 AN: 39442

South Asian (SAS) AF: 0.165 AC: 14098 AN: 85202

European-Finnish (FIN) AF: 0.249 AC: 13270 AN: 53332

Middle Eastern (MID) AF: 0.273 AC: 1545 AN: 5656

European-Non Finnish (NFE) AF: 0.324 AC: 344663 AN: 1064274

Other (OTH) AF: 0.294 AC: 17264 AN: 58626

GnomAD4 genome AF: 0.308 AC: 46764 AN: 151978 Hom.: 7687 Cov.: 32 AF XY: 0.298 AC XY: 22167 AN XY: 74272

African (AFR) AF: 0.349 AC: 14444 AN: 41442

American (AMR) AF: 0.318 AC: 4860 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.359 AC: 1245 AN: 3470

East Asian (EAS) AF: 0.00252 AC: 13 AN: 5158

South Asian (SAS) AF: 0.156 AC: 751 AN: 4818

European-Finnish (FIN) AF: 0.237 AC: 2507 AN: 10596

Middle Eastern (MID) AF: 0.333 AC: 98 AN: 294

European-Non Finnish (NFE) AF: 0.321 AC: 21772 AN: 67902

Other (OTH) AF: 0.310 AC: 655 AN: 2110

Alfa AF: 0.316 Hom.: 13404

Bravo AF: 0.317

Asia WGS AF: 0.102 AC: 353 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	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	-0.87
CADD	Benign	0.010
DANN	Benign	0.40
PhyloP100		-2.0
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: rs4791765; hg19: chr17-8784361; COSMIC: COSV52650685;