Variant 1-46066985-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_003629.4(PIK3R3):c.421C>G(p.His141Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,104 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. H141N) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)

Consequence

PIK3R3
NM_003629.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.01

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:):

P3R3URF-PIK3R3 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.3828423).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PIK3R3	NM_003629.4 linkuse as main transcript	c.421C>G	p.His141Asp	missense_variant	4/10	ENST00000262741.10
P3R3URF-PIK3R3	NM_001303427.2 linkuse as main transcript	c.559C>G	p.His187Asp	missense_variant	4/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PIK3R3	ENST00000262741.10 linkuse as main transcript	c.421C>G	p.His141Asp	missense_variant	4/10	1	NM_003629.4	P1	Q92569-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152104

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152104

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74314

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 13, 2022

The c.421C>G (p.H141D) alteration is located in exon 4 (coding exon 4) of the PIK3R3 gene. This alteration results from a C to G substitution at nucleotide position 421, causing the histidine (H) at amino acid position 141 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.60

BayesDel_addAF

Uncertain

0.022

BayesDel_noAF

Benign

-0.21

Cadd

Pathogenic

Dann

Uncertain

0.99

DEOGEN2

Uncertain

0.64

D;D;D;.;T;.

Eigen

Benign

0.067

Eigen_PC

Uncertain

0.23

FATHMM_MKL

Uncertain

0.94

M_CAP

Benign

0.054

MetaRNN

Benign

0.38

T;T;T;T;T;T

MetaSVM

Benign

-0.66

MutationAssessor

Benign

1.4

L;L;L;L;.;.

MutationTaster

Benign

0.92

D;D;D;D;D;D;D

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-2.1

N;N;N;N;N;N

REVEL

Benign

0.19

Sift

Pathogenic

0.0

D;D;D;D;D;D

Sift4G

Pathogenic

0.0010

D;D;D;D;.;D

Polyphen

0.0040

B;B;B;B;.;.

Vest4

0.51

MutPred

0.42

.;.;.;.;.;Gain of helix (P = 0.0199);

MVP

0.81

MPC

0.16

ClinPred

0.92

GERP RS

5.4

Varity_R

0.54

gMVP

0.67

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over