chr17-8888686-C-T

Variant names:

• chr17-8888686-C-T
• rs9915880
• NM_001142633.3:c.1101G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001142633.3(PIK3R5):​c.1101G>A​(p.Ser367Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.284 in 1,613,550 control chromosomes in the GnomAD database, including 68,711 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.28 (6337 hom., cov: 33)
  • Exomes 𝑓: 0.28 (62374 hom.)
• Consequence: PIK3R5 NM_001142633.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -3.23
• Publications: 15 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

ENSG00000297004 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BP6: Variant 17-8888686-C-T is Benign according to our data. Variant chr17-8888686-C-T is described in ClinVar as Benign. ClinVar VariationId is 130136.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.23 with no splicing effect.
• 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_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.1101G>A	p.Ser367Ser	synonymous	Exon 10 of 19	NP_001136105.1	L7RT34
	PIK3R5	NM_014308.4		c.1101G>A	p.Ser367Ser	synonymous	Exon 10 of 19	NP_055123.2	Q8WYR1-1
	PIK3R5	NM_001388396.1		c.1101G>A	p.Ser367Ser	synonymous	Exon 10 of 19	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.1101G>A	p.Ser367Ser	synonymous	Exon 10 of 19	ENSP00000392812.1	Q8WYR1-1
	PIK3R5	ENST00000581552.5	TSL:1	c.1101G>A	p.Ser367Ser	synonymous	Exon 10 of 19	ENSP00000462433.1	Q8WYR1-1
	PIK3R5	ENST00000623421.3	TSL:1	c.-58G>A		5_prime_UTR	Exon 9 of 18	ENSP00000485280.1	Q8WYR1-2

Frequencies

GnomAD3 genomes AF: 0.279 AC: 42366 AN: 152122 Hom.: 6320 Cov.: 33

Gnomad AFR AF: 0.292

Gnomad AMI AF: 0.453

Gnomad AMR AF: 0.301

Gnomad ASJ AF: 0.332

Gnomad EAS AF: 0.00211

Gnomad SAS AF: 0.156

Gnomad FIN AF: 0.189

Gnomad MID AF: 0.301

Gnomad NFE AF: 0.303

Gnomad OTH AF: 0.298

GnomAD2 exomes AF: 0.247 AC: 61093 AN: 247466 AF XY: 0.244

Gnomad AFR exome AF: 0.296

Gnomad AMR exome AF: 0.243

Gnomad ASJ exome AF: 0.323

Gnomad EAS exome AF: 0.000707

Gnomad FIN exome AF: 0.192

Gnomad NFE exome AF: 0.308

Gnomad OTH exome AF: 0.279

GnomAD4 exome AF: 0.285 AC: 416200 AN: 1461310 Hom.: 62374 Cov.: 37 AF XY: 0.280 AC XY: 203550 AN XY: 726920

African (AFR) AF: 0.291 AC: 9754 AN: 33478

American (AMR) AF: 0.251 AC: 11209 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.319 AC: 8348 AN: 26130

East Asian (EAS) AF: 0.000730 AC: 29 AN: 39700

South Asian (SAS) AF: 0.165 AC: 14266 AN: 86254

European-Finnish (FIN) AF: 0.207 AC: 10980 AN: 53090

Middle Eastern (MID) AF: 0.250 AC: 1444 AN: 5768

European-Non Finnish (NFE) AF: 0.309 AC: 343554 AN: 1111804

Other (OTH) AF: 0.275 AC: 16616 AN: 60380

GnomAD4 genome AF: 0.279 AC: 42418 AN: 152240 Hom.: 6337 Cov.: 33 AF XY: 0.268 AC XY: 19966 AN XY: 74448

African (AFR) AF: 0.292 AC: 12145 AN: 41530

American (AMR) AF: 0.301 AC: 4611 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.332 AC: 1153 AN: 3472

East Asian (EAS) AF: 0.00212 AC: 11 AN: 5192

South Asian (SAS) AF: 0.154 AC: 743 AN: 4822

European-Finnish (FIN) AF: 0.189 AC: 2009 AN: 10610

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

European-Non Finnish (NFE) AF: 0.303 AC: 20621 AN: 68000

Other (OTH) AF: 0.296 AC: 624 AN: 2110

Alfa AF: 0.294 Hom.: 9548

Bravo AF: 0.288

Asia WGS AF: 0.0920 AC: 321 AN: 3478

EpiCase AF: 0.307

EpiControl AF: 0.310

ClinVar

ClinVar submissions

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	-0.66
CADD	Benign	2.6
DANN	Benign	0.86
PhyloP100		-3.2
Mutation Taster		=59/41	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs9915880; hg19: chr17-8792003; COSMIC: COSV52653907; COSMIC: COSV52653907;