rs797045887

chr17-8890812-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001142633.3(PIK3R5):c.583A>G(p.Thr195Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,460,924 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PIK3R5 NM_001142633.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 3.02

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]

LOC124903922 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PIK3R5	NM_001142633.3	c.583A>G	p.Thr195Ala	missense_variant	7/19	ENST00000447110.6
LOC124903922	XR_007065613.1	n.80-976T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PIK3R5	ENST00000447110.6	c.583A>G	p.Thr195Ala	missense_variant	7/19	5	NM_001142633.3	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1460924 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726632

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 24, 2022	The c.583A>G (p.T195A) alteration is located in exon 7 (coding exon 6) of the PIK3R5 gene. This alteration results from a A to G substitution at nucleotide position 583, causing the threonine (T) at amino acid position 195 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jul 31, 2015	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Uncertain	0.034	T
BayesDel_noAF	Benign	-0.19
Cadd	Uncertain	25
Dann	Benign	0.90
DEOGEN2	Uncertain	0.50	D;D;.
Eigen	Benign	0.071
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.65	T;.;T
M_CAP	Benign	0.046	D
MetaRNN	Uncertain	0.56	D;D;D
MetaSVM	Benign	-0.59	T
MutationAssessor	Uncertain	2.6	M;M;.
MutationTaster	Benign	0.97	D;D;D
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-2.1	N;.;.
REVEL	Uncertain	0.35
Sift	Benign	0.34	T;.;.
Sift4G	Uncertain	0.044	D;D;D
Polyphen		0.47	P;P;.
Vest4		0.64
MutPred		0.54		Gain of helix (P = 0.132);Gain of helix (P = 0.132);Gain of helix (P = 0.132);
MVP		0.73
MPC		0.81
ClinPred		0.55	D
GERP RS		5.2
Varity_R		0.080
gMVP		0.38

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: rs797045887; hg19: chr17-8794129;