rs394811

Variant names:

• chr17-8889197-G-A
• rs394811
• NM_001142633.3:c.837C>T

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.837C>T​(p.His279His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.416 in 1,611,776 control chromosomes in the GnomAD database, including 144,278 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.47 (18266 hom., cov: 33)
  • Exomes 𝑓: 0.41 (126012 hom.)
• Consequence: PIK3R5 NM_001142633.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.395
• Publications: 24 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BP6: Variant 17-8889197-G-A is Benign according to our data. Variant chr17-8889197-G-A is described in ClinVar as Benign. ClinVar VariationId is 129894.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.658 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.837C>T	p.His279His	synonymous	Exon 9 of 19	NP_001136105.1	L7RT34
	PIK3R5	NM_014308.4		c.837C>T	p.His279His	synonymous	Exon 9 of 19	NP_055123.2	Q8WYR1-1
	PIK3R5	NM_001388396.1		c.837C>T	p.His279His	synonymous	Exon 9 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.837C>T	p.His279His	synonymous	Exon 9 of 19	ENSP00000392812.1	Q8WYR1-1
	PIK3R5	ENST00000581552.5	TSL:1	c.837C>T	p.His279His	synonymous	Exon 9 of 19	ENSP00000462433.1	Q8WYR1-1
	PIK3R5	ENST00000623421.3	TSL:1	c.-322C>T		5_prime_UTR	Exon 8 of 18	ENSP00000485280.1	Q8WYR1-2

Frequencies

GnomAD3 genomes AF: 0.469 AC: 71263 AN: 151990 Hom.: 18217 Cov.: 33

Gnomad AFR AF: 0.664

Gnomad AMI AF: 0.509

Gnomad AMR AF: 0.440

Gnomad ASJ AF: 0.505

Gnomad EAS AF: 0.174

Gnomad SAS AF: 0.418

Gnomad FIN AF: 0.290

Gnomad MID AF: 0.544

Gnomad NFE AF: 0.408

Gnomad OTH AF: 0.472

GnomAD2 exomes AF: 0.401 AC: 100147 AN: 249744 AF XY: 0.398

Gnomad AFR exome AF: 0.674

Gnomad AMR exome AF: 0.386

Gnomad ASJ exome AF: 0.496

Gnomad EAS exome AF: 0.166

Gnomad FIN exome AF: 0.293

Gnomad NFE exome AF: 0.412

Gnomad OTH exome AF: 0.414

GnomAD4 exome AF: 0.411 AC: 599225 AN: 1459668 Hom.: 126012 Cov.: 37 AF XY: 0.409 AC XY: 297278 AN XY: 726190

African (AFR) AF: 0.676 AC: 22593 AN: 33444

American (AMR) AF: 0.394 AC: 17575 AN: 44600

Ashkenazi Jewish (ASJ) AF: 0.494 AC: 12883 AN: 26078

East Asian (EAS) AF: 0.193 AC: 7674 AN: 39678

South Asian (SAS) AF: 0.420 AC: 36221 AN: 86144

European-Finnish (FIN) AF: 0.303 AC: 16181 AN: 53330

Middle Eastern (MID) AF: 0.446 AC: 2565 AN: 5754

European-Non Finnish (NFE) AF: 0.413 AC: 458059 AN: 1110314

Other (OTH) AF: 0.422 AC: 25474 AN: 60326

GnomAD4 genome AF: 0.469 AC: 71369 AN: 152108 Hom.: 18266 Cov.: 33 AF XY: 0.459 AC XY: 34137 AN XY: 74368

African (AFR) AF: 0.665 AC: 27570 AN: 41474

American (AMR) AF: 0.440 AC: 6732 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.505 AC: 1752 AN: 3470

East Asian (EAS) AF: 0.175 AC: 904 AN: 5178

South Asian (SAS) AF: 0.417 AC: 2009 AN: 4822

European-Finnish (FIN) AF: 0.290 AC: 3073 AN: 10590

Middle Eastern (MID) AF: 0.548 AC: 161 AN: 294

European-Non Finnish (NFE) AF: 0.408 AC: 27708 AN: 67960

Other (OTH) AF: 0.472 AC: 996 AN: 2112

Alfa AF: 0.447 Hom.: 37388

Bravo AF: 0.486

Asia WGS AF: 0.298 AC: 1037 AN: 3478

EpiCase AF: 0.417

EpiControl AF: 0.419

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	-0.69
CADD	Benign	5.7
DANN	Benign	0.31
PhyloP100		0.40
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs394811; hg19: chr17-8792514; COSMIC: COSV52653522; COSMIC: COSV52653522;