chr17-8880725-G-A

Variant names:

• chr17-8880725-G-A
• rs62620227
• NM_001142633.3:c.2557C>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_001142633.3(PIK3R5):​c.2557C>T​(p.Pro853Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00345 in 1,613,940 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0027 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0035 (16 hom.)
• Consequence: PIK3R5 NM_001142633.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: -0.833
• Publications: 3 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0077055395).
• BP6: Variant 17-8880725-G-A is Benign according to our data. Variant chr17-8880725-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 211906.
• BS2: High Homozygotes in GnomAdExome4 at 16 AR gene

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.2557C>T	p.Pro853Ser	missense	Exon 19 of 19	NP_001136105.1	L7RT34
	PIK3R5	NM_014308.4		c.2557C>T	p.Pro853Ser	missense	Exon 19 of 19	NP_055123.2	Q8WYR1-1
	PIK3R5	NM_001388396.1		c.2554C>T	p.Pro852Ser	missense	Exon 19 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.2557C>T	p.Pro853Ser	missense	Exon 19 of 19	ENSP00000392812.1	Q8WYR1-1
	PIK3R5	ENST00000581552.5	TSL:1	c.2557C>T	p.Pro853Ser	missense	Exon 19 of 19	ENSP00000462433.1	Q8WYR1-1
	PIK3R5	ENST00000623421.3	TSL:1	c.1399C>T	p.Pro467Ser	missense	Exon 18 of 18	ENSP00000485280.1	Q8WYR1-2

Frequencies

GnomAD3 genomes AF: 0.00275 AC: 418 AN: 152186 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00327

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00248

Gnomad FIN AF: 0.00508

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00370

Gnomad OTH AF: 0.00383

GnomAD2 exomes AF: 0.00297 AC: 741 AN: 249854 AF XY: 0.00308

Gnomad AFR exome AF: 0.000616

Gnomad AMR exome AF: 0.00281

Gnomad ASJ exome AF: 0.00109

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00456

Gnomad NFE exome AF: 0.00407

Gnomad OTH exome AF: 0.00131

GnomAD4 exome AF: 0.00352 AC: 5144 AN: 1461636 Hom.: 16 Cov.: 31 AF XY: 0.00353 AC XY: 2568 AN XY: 727106

African (AFR) AF: 0.000657 AC: 22 AN: 33478

American (AMR) AF: 0.00291 AC: 130 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.000995 AC: 26 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00194 AC: 167 AN: 86234

European-Finnish (FIN) AF: 0.00348 AC: 186 AN: 53384

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00399 AC: 4431 AN: 1111880

Other (OTH) AF: 0.00300 AC: 181 AN: 60366

GnomAD4 genome AF: 0.00274 AC: 418 AN: 152304 Hom.: 0 Cov.: 32 AF XY: 0.00306 AC XY: 228 AN XY: 74478

African (AFR) AF: 0.000963 AC: 40 AN: 41552

American (AMR) AF: 0.00327 AC: 50 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00248 AC: 12 AN: 4832

European-Finnish (FIN) AF: 0.00508 AC: 54 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00370 AC: 252 AN: 68024

Other (OTH) AF: 0.00379 AC: 8 AN: 2112

Alfa AF: 0.00342 Hom.: 3

Bravo AF: 0.00252

TwinsUK AF: 0.00351 AC: 13

ALSPAC AF: 0.00311 AC: 12

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00488 AC: 42

ExAC AF: 0.00280 AC: 340

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00365

EpiControl AF: 0.00421

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	1	-	Ataxia with oculomotor apraxia type 3 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	0.028
DANN	Benign	0.38
DEOGEN2	Benign	0.11	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.43	T
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.0077	T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	0.18	N
PhyloP100		-0.83
PrimateAI	Benign	0.27	T
PROVEAN	Benign	0.71	N
REVEL	Benign	0.10
Sift	Benign	0.50	T
Sift4G	Benign	0.45	T
Polyphen		0.0	B
Vest4		0.029
MVP		0.18
MPC		0.48
ClinPred		0.00090	T
GERP RS		-5.6
Varity_R		0.017
gMVP		0.16
Mutation Taster		=100/0	polymorphism

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: rs62620227; hg19: chr17-8784042; COSMIC: COSV107292099;