Genetic Variant PIK3R3:p.Ala92Gly (chr1-46077554-G-C) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_003629.4(PIK3R3):c.275C>G(p.Ala92Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. A92V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

PIK3R3
NM_003629.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 10.0

Publications

0 publications found

Variant links:

Genes affected

PIK3R3 (HGNC:8981): (phosphoinositide-3-kinase regulatory subunit 3) Phosphatidylinositol 3-kinase (PI3K) phosphorylates phosphatidylinositol and similar compounds, which then serve as second messengers in growth signaling pathways. PI3K is composed of a catalytic and a regulatory subunit. The protein encoded by this gene represents a regulatory subunit of PI3K. The encoded protein contains two SH2 domains through which it binds activated protein tyrosine kinases to regulate their activity. [provided by RefSeq, Jun 2016]

PIK3R3 links:

P3R3URF-PIK3R3 (HGNC:54999): (P3R3URF-PIK3R3 readthrough) This locus represents naturally occurring readthrough transcription between the neighboring genes LOC110117498 and PIK3R3. The readthrough transcript encodes a fusion protein that shares sequence identity with each individual gene product. [provided by RefSeq, Apr 2017]

P3R3URF-PIK3R3 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.875

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003629.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PIK3R3	NM_003629.4	MANE Select	c.275C>G	p.Ala92Gly	missense	Exon 3 of 10	NP_003620.3
P3R3URF-PIK3R3	NM_001303427.2		c.413C>G	p.Ala138Gly	missense	Exon 3 of 10	NP_001290356.1	F6TDL0
PIK3R3	NM_001303428.1		c.326C>G	p.Ala109Gly	missense	Exon 4 of 11	NP_001290357.1	B4DXM8

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PIK3R3	ENST00000262741.10	TSL:1 MANE Select	c.275C>G	p.Ala92Gly	missense	Exon 3 of 10	ENSP00000262741.5	Q92569-1
P3R3URF-PIK3R3	ENST00000540385.2	TSL:2	c.413C>G	p.Ala138Gly	missense	Exon 3 of 10	ENSP00000439913.1	F6TDL0
PIK3R3	ENST00000372006.5	TSL:1	c.275C>G	p.Ala92Gly	missense	Exon 4 of 11	ENSP00000361075.1	Q92569-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.32

BayesDel_noAF

Pathogenic

0.22

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.79

Eigen

Pathogenic

0.71

Eigen_PC

Pathogenic

0.72

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.95

M_CAP

Benign

0.065

MetaRNN

Pathogenic

0.88

MetaSVM

Uncertain

0.70

MutationAssessor

Uncertain

2.3

PhyloP100

PrimateAI

Pathogenic

0.79

PROVEAN

Uncertain

-3.2

REVEL

Pathogenic

0.84

Sift

Benign

0.035

Sift4G

Uncertain

0.047

Polyphen

1.0

Vest4

0.87

MutPred

0.74

Gain of disorder (P = 0.0418)

MVP

0.98

MPC

0.55

ClinPred

0.98

GERP RS

5.0

Varity_R

0.45

gMVP

0.58

Mutation Taster

=29/71

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over