chr17-8880727-G-A

Variant names:

• chr17-8880727-G-A
• rs148129311
• NM_001142633.3:c.2555C>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001142633.3(PIK3R5):​c.2555C>T​(p.Thr852Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000263 in 1,613,962 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T852A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00027 (2 hom.)
• Consequence: PIK3R5 NM_001142633.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.118

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]

LOC124903919 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.05252403).
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIK3R5	NM_001142633.3	c.2555C>T	p.Thr852Met	missense_variant	Exon 19 of 19	ENST00000447110.6	NP_001136105.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PIK3R5	ENST00000447110.6	c.2555C>T	p.Thr852Met	missense_variant	Exon 19 of 19	5	NM_001142633.3	ENSP00000392812.1

Frequencies

GnomAD3 genomes AF: 0.000217 AC: 33 AN: 152224 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000523

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000323

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000216 AC: 54 AN: 249816 AF XY: 0.000252

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.000203

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000302

Gnomad OTH exome AF: 0.000491

GnomAD4 exome AF: 0.000268 AC: 392 AN: 1461620 Hom.: 2 Cov.: 31 AF XY: 0.000274 AC XY: 199 AN XY: 727098

Gnomad4 AFR exome AF: 0.0000299 AC: 1 AN: 33476

Gnomad4 AMR exome AF: 0.000179 AC: 8 AN: 44694

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 26128

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39700

Gnomad4 SAS exome AF: 0.000359 AC: 31 AN: 86232

Gnomad4 FIN exome AF: 0.0000187 AC: 1 AN: 53384

Gnomad4 NFE exome AF: 0.000303 AC: 337 AN: 1111870

Gnomad4 Remaining exome AF: 0.000166 AC: 10 AN: 60370

GnomAD4 genome AF: 0.000217 AC: 33 AN: 152342 Hom.: 0 Cov.: 32 AF XY: 0.000161 AC XY: 12 AN XY: 74490

Gnomad4 AFR AF: 0.0000481 AC: 0.0000481024 AN: 0.0000481024

Gnomad4 AMR AF: 0.000523 AC: 0.000522603 AN: 0.000522603

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.000207 AC: 0.000207039 AN: 0.000207039

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.000323 AC: 0.000323406 AN: 0.000323406

Gnomad4 OTH AF: 0.00 AC: 0 AN: 0

Alfa AF: 0.000278 Hom.: 0

Bravo AF: 0.000246

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000222 AC: 27

EpiCase AF: 0.000436

EpiControl AF: 0.000652

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Ataxia with oculomotor apraxia type 3 Uncertain:1

Oct 07, 2022

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	5.2
DANN	Benign	0.64
DEOGEN2	Benign	0.17	T;.;.;.;T;.
Eigen	Benign	-0.99
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.36	T;.;.;T;.;T
M_CAP	Benign	0.044	D
MetaRNN	Benign	0.053	T;T;T;T;T;T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	0.0	N;.;.;.;N;.
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.080	N;.;.;.;.;.
REVEL	Benign	0.20
Sift	Benign	0.085	T;.;.;.;.;.
Sift4G	Uncertain	0.050	T;T;T;T;T;T
Polyphen		0.70	P;.;.;.;P;.
Vest4		0.080
MVP		0.13
MPC		0.81
ClinPred		0.014	T
GERP RS		-1.6
Varity_R		0.021
gMVP		0.19
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs148129311; hg19: chr17-8784044; COSMIC: COSV52650795;