rs61761068

Positions:

• chr17-8887116-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_001142633.3(PIK3R5):​c.1885C>T​(p.Pro629Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00152 in 1,614,038 control chromosomes in the GnomAD database, including 30 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0079 (17 hom., cov: 32)
  • Exomes 𝑓: 0.00086 (13 hom.)
• Consequence: PIK3R5 NM_001142633.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2 B:2
• Conservation: PhyloP100: 6.31

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008457243).
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00791 (1205/152308) while in subpopulation AFR AF= 0.0267 (1110/41560). AF 95% confidence interval is 0.0254. There are 17 homozygotes in gnomad4. There are 574 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 17 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PIK3R5	NM_001142633.3	c.1885C>T	p.Pro629Ser	missense_variant	12/19	ENST00000447110.6	NP_001136105.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PIK3R5	ENST00000447110.6	c.1885C>T	p.Pro629Ser	missense_variant	12/19	5	NM_001142633.3	ENSP00000392812	P4

Frequencies

GnomAD3 genomes AF: 0.00790 AC: 1203 AN: 152190 Hom.: 18 Cov.: 32

Gnomad AFR AF: 0.0267

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00425

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00621

GnomAD3 exomes AF: 0.00226 AC: 568 AN: 250856 Hom.: 7 AF XY: 0.00160 AC XY: 217 AN XY: 135668

Gnomad AFR exome AF: 0.0292

Gnomad AMR exome AF: 0.00220

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000106

Gnomad OTH exome AF: 0.000980

GnomAD4 exome AF: 0.000859 AC: 1256 AN: 1461730 Hom.: 13 Cov.: 32 AF XY: 0.000719 AC XY: 523 AN XY: 727164

Gnomad4 AFR exome AF: 0.0278

Gnomad4 AMR exome AF: 0.00242

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000612

Gnomad4 OTH exome AF: 0.00232

GnomAD4 genome AF: 0.00791 AC: 1205 AN: 152308 Hom.: 17 Cov.: 32 AF XY: 0.00771 AC XY: 574 AN XY: 74480

Gnomad4 AFR AF: 0.0267

Gnomad4 AMR AF: 0.00425

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.00615

Alfa AF: 0.00255 Hom.: 4

Bravo AF: 0.00916

ESP6500AA AF: 0.0263 AC: 116

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00263 AC: 319

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000382

EpiControl AF: 0.000296

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:2 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Ataxia with oculomotor apraxia type 3 Pathogenic:1 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Uncertain significance, no assertion criteria provided	curation	Reproductive Health Research and Development, BGI Genomics	Jan 06, 2020	NM_001142633.2:c.1885C>T in the PIK3R5 gene has an allele frequency of 0.029 in African subpopulation in the gnomAD database. This variant has been detected in a consanguineous family with autosomal recessive ataxias, segregating with phenotypes (PMID: 22065524). We interpret it as variant of uncertain significance (VUS). ACMG/AMP criteria applied: BS1, PP1, PP4. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 01, 2012	- -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 09, 2024	Variant summary: PIK3R5 c.1885C>T (p.Pro629Ser) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0023 in 250856 control chromosomes, predominantly at a frequency of 0.029 within the African or African-American subpopulation in the gnomAD database, including 7 homozygotes, strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.1885C>T has been reported in the literature in individuals affected with Ataxia With Oculomotor Apraxia, unspecified disease conditions and healthy donors (example, AlTassan_2012, Capalbo_2019). These report(s) do not provide unequivocal conclusions about association of the variant with Ataxia With Oculomotor Apraxia Type 3. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 22065524, 31589614). ClinVar contains an entry for this variant (Variation ID: 48651). Based on the evidence outlined above, the variant was classified as likely benign. -
Benign, criteria provided, single submitter	research	H3Africa Consortium	Oct 28, 2020	While the frequency of the alternate allele in gnoMAD v2.0.2 is 0.051, its frequency in African populations is >5%. This suggests that previous classifications of this variant as pathogenic are in error. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.21
CADD	Uncertain	24
DANN	Benign	0.94
DEOGEN2	Uncertain	0.46	T;.;.;.;T;.
Eigen	Uncertain	0.21
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.84	T;.;.;T;.;T
MetaRNN	Benign	0.0085	T;T;T;T;T;T
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	1.8	L;.;.;.;L;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-2.3	N;.;.;.;.;.
REVEL	Uncertain	0.43
Sift	Benign	0.36	T;.;.;.;.;.
Sift4G	Benign	0.14	T;T;T;T;T;T
Polyphen		0.92	P;.;.;.;P;.
Vest4		0.57
MVP		0.36
MPC		1.0
ClinPred		0.054	T
GERP RS		4.7
Varity_R		0.19
gMVP		0.73

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

Publications

LitVar

Other links and lift over

dbSNP: rs61761068; hg19: chr17-8790433;