rs753534655

Variant names:

• chr1-46077554-G-A
• rs753534655
• NM_003629.4:c.275C>T

Your query was ambiguous. Multiple possible variants found:

• chr1-46077554-G-A
• chr1-46077554-G-C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PP3_Moderate BS2

The NM_003629.4(PIK3R3):​c.275C>T​(p.Ala92Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000219 in 1,460,094 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. A92G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000022 (0 hom.)
• Consequence: PIK3R3 NM_003629.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 10.0
• Publications: 1 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: Likely_benign. The variant received -2 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.874
• BS2: High AC in GnomAdExome4 at 32 AD gene.

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.275C>T	p.Ala92Val	missense	Exon 3 of 10	NP_003620.3
	P3R3URF-PIK3R3	NM_001303427.2		c.413C>T	p.Ala138Val	missense	Exon 3 of 10	NP_001290356.1	F6TDL0
	PIK3R3	NM_001303428.1		c.326C>T	p.Ala109Val	missense	Exon 4 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.275C>T	p.Ala92Val	missense	Exon 3 of 10	ENSP00000262741.5	Q92569-1
	P3R3URF-PIK3R3	ENST00000540385.2	TSL:2	c.413C>T	p.Ala138Val	missense	Exon 3 of 10	ENSP00000439913.1	F6TDL0
	PIK3R3	ENST00000372006.5	TSL:1	c.275C>T	p.Ala92Val	missense	Exon 4 of 11	ENSP00000361075.1	Q92569-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000119 AC: 3 AN: 251354 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000219 AC: 32 AN: 1460094 Hom.: 0 Cov.: 28 AF XY: 0.0000179 AC XY: 13 AN XY: 726484

African (AFR) AF: 0.00 AC: 0 AN: 33446

American (AMR) AF: 0.00 AC: 0 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39666

South Asian (SAS) AF: 0.00 AC: 0 AN: 86204

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53376

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

European-Non Finnish (NFE) AF: 0.0000279 AC: 31 AN: 1110476

Other (OTH) AF: 0.0000166 AC: 1 AN: 60324

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

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	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.79	D
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.079	D
MetaRNN	Pathogenic	0.87	D
MetaSVM	Uncertain	0.78	D
MutationAssessor	Pathogenic	3.4	M
PhyloP100		10
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-3.5	D
REVEL	Pathogenic	0.93
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.96
MutPred		0.69		Gain of catalytic residue at A138 (P = 0.0629)
MVP		0.99
MPC		0.54
ClinPred		0.98	D
GERP RS		5.0
Varity_R		0.67
gMVP		0.73
Mutation Taster		=26/74	disease causing

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: rs753534655; hg19: chr1-46543226; COSMIC: COSV53107359;