rs1258531788

Variant names:

• chr1-46043801-T-C
• rs1258531788
• NM_003629.4:c.1258A>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_003629.4(PIK3R3):​c.1258A>G​(p.Asn420Asp) variant causes a missense change. The variant allele was found at a frequency of 0.00000186 in 1,614,040 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. N420S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PIK3R3 NM_003629.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.04
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.37659013).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIK3R3	NM_003629.4	MANE Select	c.1258A>G	p.Asn420Asp	missense	Exon 10 of 10	NP_003620.3
	P3R3URF-PIK3R3	NM_001303427.2		c.1396A>G	p.Asn466Asp	missense	Exon 10 of 10	NP_001290356.1	F6TDL0
	PIK3R3	NM_001303428.1		c.1309A>G	p.Asn437Asp	missense	Exon 11 of 11	NP_001290357.1	B4DXM8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIK3R3	ENST00000262741.10	TSL:1 MANE Select	c.1258A>G	p.Asn420Asp	missense	Exon 10 of 10	ENSP00000262741.5	Q92569-1
	P3R3URF-PIK3R3	ENST00000540385.2	TSL:2	c.1396A>G	p.Asn466Asp	missense	Exon 10 of 10	ENSP00000439913.1	F6TDL0
	PIK3R3	ENST00000372006.5	TSL:1	c.1258A>G	p.Asn420Asp	missense	Exon 11 of 11	ENSP00000361075.1	Q92569-1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152202 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000796 AC: 2 AN: 251358 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461838 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727218

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111972

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152202 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74368

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41464

American (AMR) AF: 0.0000654 AC: 1 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2088

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Benign	-0.068	T
BayesDel_noAF	Benign	-0.25
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.75	D
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Benign	0.20	N
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.38	T
MetaSVM	Uncertain	0.54	D
MutationAssessor	Benign	1.2	L
PhyloP100		5.0
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-3.6	D
REVEL	Uncertain	0.43
Sift	Benign	0.087	T
Sift4G	Benign	0.12	T
Polyphen		0.98	D
Vest4		0.34
MutPred		0.48		Loss of catalytic residue at N466 (P = 0.0357)
MVP		0.95
MPC		0.58
ClinPred		0.63	D
GERP RS		6.0
Varity_R		0.64
gMVP		0.56
Mutation Taster		=57/43	polymorphism

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

Other links and lift over

dbSNP: rs1258531788; hg19: chr1-46509473;