1-46080722-C-T

Position:

• chr1-46080722-C-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_001328648.1(PIK3R3):​c.3G>A​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PIK3R3 NM_001328648.1 start_lost
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.05

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]

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]

PIK3R3 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PIK3R3	NM_003629.4	c.135G>A	p.Met45Ile	missense_variant	2/10	ENST00000262741.10	NP_003620.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PIK3R3	ENST00000262741.10	c.135G>A	p.Met45Ile	missense_variant	2/10	1	NM_003629.4	ENSP00000262741.5
P3R3URF-PIK3R3	ENST00000540385.2	c.273G>A	p.Met91Ile	missense_variant	2/10	2		ENSP00000439913.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 05, 2024

The c.135G>A (p.M45I) alteration is located in exon 2 (coding exon 2) of the PIK3R3 gene. This alteration results from a G to A substitution at nucleotide position 135, causing the methionine (M) at amino acid position 45 to be replaced by an isoleucine (I). 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	Benign	0.091
BayesDel_addAF	Benign	-0.058	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	20
DANN	Benign	0.91
DEOGEN2	Benign	0.12	T;T;T;.;T;.
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.17
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.38	.;.;T;T;T;T
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.15	T;T;T;T;T;T
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	1.9	M;M;M;M;.;.
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.090	N;N;N;N;N;N
REVEL	Benign	0.13
Sift	Benign	0.75	T;T;T;T;T;T
Sift4G	Benign	0.69	T;T;T;T;.;T
Polyphen		0.0	B;B;B;B;.;.
Vest4		0.22
MutPred		0.28		.;.;.;.;.;Loss of catalytic residue at M91 (P = 0.0132);
MVP		0.80
MPC		0.12
ClinPred		0.66	D
GERP RS		3.2
Varity_R		0.051
gMVP		0.19

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-46546394;