NM_003629.4:c.1192G>A

Variant names:

• chr1-46043867-C-T
• rs755888231
• NM_003629.4:c.1192G>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_003629.4(PIK3R3):​c.1192G>A​(p.Asp398Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0000267 in 1,612,516 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. D398H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000028 (0 hom.)
• Consequence: PIK3R3 NM_003629.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.82
• Publications: 2 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 -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.13607866).
• BS2: High AC in GnomAdExome4 at 41 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.1192G>A	p.Asp398Asn	missense	Exon 10 of 10	NP_003620.3
	P3R3URF-PIK3R3	NM_001303427.2		c.1330G>A	p.Asp444Asn	missense	Exon 10 of 10	NP_001290356.1	F6TDL0
	PIK3R3	NM_001303428.1		c.1243G>A	p.Asp415Asn	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.1192G>A	p.Asp398Asn	missense	Exon 10 of 10	ENSP00000262741.5	Q92569-1
	P3R3URF-PIK3R3	ENST00000540385.2	TSL:2	c.1330G>A	p.Asp444Asn	missense	Exon 10 of 10	ENSP00000439913.1	F6TDL0
	PIK3R3	ENST00000372006.5	TSL:1	c.1192G>A	p.Asp398Asn	missense	Exon 11 of 11	ENSP00000361075.1	Q92569-1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152138 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000385

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: 0.0000443 AC: 11 AN: 248062 AF XY: 0.0000597

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000548

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000281 AC: 41 AN: 1460378 Hom.: 0 Cov.: 31 AF XY: 0.0000358 AC XY: 26 AN XY: 726324

African (AFR) AF: 0.0000299 AC: 1 AN: 33452

American (AMR) AF: 0.00 AC: 0 AN: 44484

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26100

East Asian (EAS) AF: 0.00 AC: 0 AN: 39656

South Asian (SAS) AF: 0.000442 AC: 38 AN: 86070

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53350

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

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111148

Other (OTH) AF: 0.00 AC: 0 AN: 60352

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152138 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74318

African (AFR) AF: 0.00 AC: 0 AN: 41424

American (AMR) AF: 0.00 AC: 0 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000385 AC: 2 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68014

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000247 AC: 3

Asia WGS AF: 0.000289 AC: 1 AN: 3478

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	Benign	0.083
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.35
CADD	Uncertain	25
DANN	Benign	0.96
DEOGEN2	Benign	0.26	T
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.035
FATHMM_MKL	Benign	0.51	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.060	D
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-0.38	T
MutationAssessor	Benign	0.34	N
PhyloP100		4.8
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-1.2	N
REVEL	Uncertain	0.37
Sift	Benign	0.75	T
Sift4G	Benign	0.97	T
Polyphen		0.023	B
Vest4		0.29
MutPred		0.54		Loss of helix (P = 0.028)
MVP		0.96
MPC		0.40
ClinPred		0.13	T
GERP RS		5.6
Varity_R		0.15
gMVP		0.35
Mutation Taster		=68/32	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: rs755888231; hg19: chr1-46509539;