1-46055887-A-T

Variant names:

• chr1-46055887-A-T
• rs785467
• NM_003629.4:c.849T>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_003629.4(PIK3R3):​c.849T>A​(p.Asn283Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.702 in 1,607,792 control chromosomes in the GnomAD database, including 397,227 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.72 (38932 hom., cov: 29)
  • Exomes 𝑓: 0.70 (358295 hom.)
• Consequence: PIK3R3 NM_003629.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.16
• Publications: 43 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=3.530216E-6).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.743 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIK3R3	NM_003629.4	MANE Select	c.849T>A	p.Asn283Lys	missense	Exon 7 of 10	NP_003620.3
	P3R3URF-PIK3R3	NM_001303427.2		c.987T>A	p.Asn329Lys	missense	Exon 7 of 10	NP_001290356.1
	PIK3R3	NM_001303428.1		c.900T>A	p.Asn300Lys	missense	Exon 8 of 11	NP_001290357.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIK3R3	ENST00000262741.10	TSL:1 MANE Select	c.849T>A	p.Asn283Lys	missense	Exon 7 of 10	ENSP00000262741.5
	P3R3URF-PIK3R3	ENST00000540385.2	TSL:2	c.987T>A	p.Asn329Lys	missense	Exon 7 of 10	ENSP00000439913.1
	PIK3R3	ENST00000372006.5	TSL:1	c.849T>A	p.Asn283Lys	missense	Exon 8 of 11	ENSP00000361075.1

Frequencies

GnomAD3 genomes AF: 0.716 AC: 108444 AN: 151562 Hom.: 38918 Cov.: 29

Gnomad AFR AF: 0.750

Gnomad AMI AF: 0.699

Gnomad AMR AF: 0.685

Gnomad ASJ AF: 0.713

Gnomad EAS AF: 0.669

Gnomad SAS AF: 0.610

Gnomad FIN AF: 0.744

Gnomad MID AF: 0.634

Gnomad NFE AF: 0.709

Gnomad OTH AF: 0.692

GnomAD2 exomes AF: 0.694 AC: 172601 AN: 248776 AF XY: 0.691

Gnomad AFR exome AF: 0.748

Gnomad AMR exome AF: 0.667

Gnomad ASJ exome AF: 0.712

Gnomad EAS exome AF: 0.675

Gnomad FIN exome AF: 0.739

Gnomad NFE exome AF: 0.709

Gnomad OTH exome AF: 0.687

GnomAD4 exome AF: 0.700 AC: 1019577 AN: 1456112 Hom.: 358295 Cov.: 32 AF XY: 0.698 AC XY: 506170 AN XY: 724768

African (AFR) AF: 0.745 AC: 24732 AN: 33190

American (AMR) AF: 0.666 AC: 29501 AN: 44296

Ashkenazi Jewish (ASJ) AF: 0.706 AC: 18383 AN: 26044

East Asian (EAS) AF: 0.685 AC: 27126 AN: 39576

South Asian (SAS) AF: 0.617 AC: 52994 AN: 85942

European-Finnish (FIN) AF: 0.733 AC: 38827 AN: 52954

Middle Eastern (MID) AF: 0.639 AC: 3675 AN: 5750

European-Non Finnish (NFE) AF: 0.706 AC: 782340 AN: 1108178

Other (OTH) AF: 0.698 AC: 41999 AN: 60182

GnomAD4 genome AF: 0.715 AC: 108493 AN: 151680 Hom.: 38932 Cov.: 29 AF XY: 0.715 AC XY: 52957 AN XY: 74106

African (AFR) AF: 0.750 AC: 31004 AN: 41322

American (AMR) AF: 0.685 AC: 10425 AN: 15226

Ashkenazi Jewish (ASJ) AF: 0.713 AC: 2473 AN: 3470

East Asian (EAS) AF: 0.668 AC: 3439 AN: 5150

South Asian (SAS) AF: 0.610 AC: 2920 AN: 4788

European-Finnish (FIN) AF: 0.744 AC: 7812 AN: 10496

Middle Eastern (MID) AF: 0.620 AC: 181 AN: 292

European-Non Finnish (NFE) AF: 0.709 AC: 48168 AN: 67924

Other (OTH) AF: 0.683 AC: 1436 AN: 2104

Alfa AF: 0.708 Hom.: 28728

Bravo AF: 0.715

TwinsUK AF: 0.701 AC: 2601

ALSPAC AF: 0.701 AC: 2701

ESP6500AA AF: 0.738 AC: 3252

ESP6500EA AF: 0.708 AC: 6090

ExAC AF: 0.694 AC: 84234

Asia WGS AF: 0.658 AC: 2288 AN: 3478

EpiCase AF: 0.708

EpiControl AF: 0.713

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.76	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	18
DANN	Benign	0.54
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.90
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.38	N
LIST_S2	Benign	0.32	T
MetaRNN	Benign	0.0000035	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-1.7	N
PhyloP100		1.2
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	1.0	N
REVEL	Benign	0.13
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.040
MutPred		0.46		Gain of ubiquitination at N329 (P = 0.0016)
MPC		0.13
ClinPred		0.0048	T
GERP RS		4.0
Varity_R		0.086
gMVP		0.23
Mutation Taster		=100/0	polymorphism (auto)

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: rs785467; hg19: chr1-46521559; COSMIC: COSV53106348;