1-46061926-T-TA

Variant names:

• chr1-46061926-T-TA
• rs558232322
• NM_003629.4:c.764+2dupT

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP6 BS2

The NM_003629.4(PIK3R3):​c.764+2dupT variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00378 in 1,612,306 control chromosomes in the GnomAD database, including 19 homozygotes. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.0025 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0039 (19 hom.)
• Consequence: PIK3R3 NM_003629.4 splice_donor, intron
• Clinical Significance: Likely benign no assertion criteria provided B:2
• Conservation: PhyloP100: 8.67
• 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: Likely_benign. The variant received -5 ACMG points.

• BP6: Variant 1-46061926-T-TA is Benign according to our data. Variant chr1-46061926-T-TA is described in ClinVar as Likely_benign. ClinVar VariationId is 1299992.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS2: High AC in GnomAd4 at 386 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.764+2dupT		splice_donor intron	N/A	NP_003620.3
	P3R3URF-PIK3R3	NM_001303427.2		c.902+2dupT		splice_donor intron	N/A	NP_001290356.1	F6TDL0
	PIK3R3	NM_001303428.1		c.815+2dupT		splice_donor intron	N/A	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.764+2_764+3insT		splice_donor intron	N/A	ENSP00000262741.5	Q92569-1
	P3R3URF-PIK3R3	ENST00000540385.2	TSL:2	c.902+2_902+3insT		splice_donor intron	N/A	ENSP00000439913.1	F6TDL0
	PIK3R3	ENST00000372006.5	TSL:1	c.764+2_764+3insT		splice_donor intron	N/A	ENSP00000361075.1	Q92569-1

Frequencies

GnomAD3 genomes AF: 0.00253 AC: 385 AN: 152216 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000844

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00807

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.00103

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00431

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00250 AC: 629 AN: 251118 AF XY: 0.00237

Gnomad AFR exome AF: 0.000800

Gnomad AMR exome AF: 0.000319

Gnomad ASJ exome AF: 0.00804

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000970

Gnomad NFE exome AF: 0.00422

Gnomad OTH exome AF: 0.00245

GnomAD4 exome AF: 0.00390 AC: 5701 AN: 1459972 Hom.: 19 Cov.: 30 AF XY: 0.00381 AC XY: 2765 AN XY: 726426

African (AFR) AF: 0.000538 AC: 18 AN: 33432

American (AMR) AF: 0.000269 AC: 12 AN: 44676

Ashkenazi Jewish (ASJ) AF: 0.00911 AC: 238 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39670

South Asian (SAS) AF: 0.000430 AC: 37 AN: 86138

European-Finnish (FIN) AF: 0.000880 AC: 47 AN: 53388

Middle Eastern (MID) AF: 0.00174 AC: 10 AN: 5762

European-Non Finnish (NFE) AF: 0.00465 AC: 5166 AN: 1110450

Other (OTH) AF: 0.00287 AC: 173 AN: 60332

GnomAD4 genome AF: 0.00253 AC: 386 AN: 152334 Hom.: 0 Cov.: 32 AF XY: 0.00228 AC XY: 170 AN XY: 74496

African (AFR) AF: 0.000842 AC: 35 AN: 41568

American (AMR) AF: 0.000392 AC: 6 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00807 AC: 28 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4830

European-Finnish (FIN) AF: 0.00103 AC: 11 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00431 AC: 293 AN: 68026

Other (OTH) AF: 0.00284 AC: 6 AN: 2112

Alfa AF: 0.00371 Hom.: 1

Bravo AF: 0.00241

EpiCase AF: 0.00365

EpiControl AF: 0.00350

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.7
Mutation Taster		=93/7	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.30		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.25		Position offset: -28
DS_DL_spliceai		0.30		Position offset: 3

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs558232322; hg19: chr1-46527598;