5-68273918-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_181523.3(PIK3R1):c.428-21G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.362 in 1,597,208 control chromosomes in the GnomAD database, including 109,233 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

Frequency

Genomes: 𝑓 0.29 ( 8116 hom., cov: 31)

Exomes 𝑓: 0.37 ( 101117 hom. )

Consequence

PIK3R1
NM_181523.3 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.138

Publications

23 publications found

Variant links:

Genes affected

PIK3R1 (HGNC:8979): (phosphoinositide-3-kinase regulatory subunit 1) Phosphatidylinositol 3-kinase phosphorylates the inositol ring of phosphatidylinositol at the 3-prime position. The enzyme comprises a 110 kD catalytic subunit and a regulatory subunit of either 85, 55, or 50 kD. This gene encodes the 85 kD regulatory subunit. Phosphatidylinositol 3-kinase plays an important role in the metabolic actions of insulin, and a mutation in this gene has been associated with insulin resistance. Alternative splicing of this gene results in four transcript variants encoding different isoforms. [provided by RefSeq, Jun 2011]

PIK3R1 Gene-Disease associations (from GenCC):

immunodeficiency 36 with lymphoproliferation
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
PIK3R1-related immunodeficiency and SHORT syndrome
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
SHORT syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics, ClinGen
agammaglobulinemia 7, autosomal recessive
Inheritance: AR Classification: STRONG, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen
activated PI3K-delta syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
autosomal agammaglobulinemia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

PIK3R1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

This position, referring to a specific DNA site, is a probable branch point but rather VUS (scored 4 / 10). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.65).

BP6

Variant 5-68273918-G-A is Benign according to our data. Variant chr5-68273918-G-A is described in ClinVar as Benign. ClinVar VariationId is 1271646.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.379 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_181523.3. 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
	PIK3R1	NM_181523.3	MANE Select	c.428-21G>A		intron	N/A	NP_852664.1	A0A2X0SFG1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
PIK3R1	ENST00000521381.6	TSL:1 MANE Select	c.428-21G>A	intron	N/A	ENSP00000428056.1	P27986-1
PIK3R1	ENST00000517412.2	TSL:1	n.1463G>A	non_coding_transcript_exon	Exon 3 of 3
PIK3R1	ENST00000697461.1		c.428-21G>A	intron	N/A	ENSP00000513319.1	P27986-4

Frequencies

GnomAD3 genomes

AF:

0.294

AC:

44694

AN:

151964

Hom.:

8120

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0735

Gnomad AMI

AF:

0.381

Gnomad AMR

AF:

0.355

Gnomad ASJ

AF:

0.353

Gnomad EAS

AF:

0.361

Gnomad SAS

AF:

0.377

Gnomad FIN

AF:

0.399

Gnomad MID

AF:

0.307

Gnomad NFE

AF:

0.383

Gnomad OTH

AF:

0.302

GnomAD2 exomes

AF:

0.363

AC:

91016

AN:

250972

AF XY:

0.367

show subpopulations

Gnomad AFR exome

AF:

0.0698

Gnomad AMR exome

AF:

0.399

Gnomad ASJ exome

AF:

0.352

Gnomad EAS exome

AF:

0.348

Gnomad FIN exome

AF:

0.405

Gnomad NFE exome

AF:

0.385

Gnomad OTH exome

AF:

0.365

GnomAD4 exome

AF:

0.370

AC:

533983

AN:

1445124

Hom.:

101117

Cov.:

AF XY:

0.371

AC XY:

267106

AN XY:

720022

show subpopulations

African (AFR)

AF:

0.0612

AC:

2025

AN:

33098

American (AMR)

AF:

0.395

AC:

17653

AN:

44698

Ashkenazi Jewish (ASJ)

AF:

0.353

AC:

9180

AN:

26012

East Asian (EAS)

AF:

0.380

AC:

15043

AN:

39604

South Asian (SAS)

AF:

0.376

AC:

32356

AN:

85946

European-Finnish (FIN)

AF:

0.408

AC:

21789

AN:

53360

Middle Eastern (MID)

AF:

0.300

AC:

1721

AN:

5740

European-Non Finnish (NFE)

AF:

0.377

AC:

413171

AN:

1096836

Other (OTH)

AF:

0.352

AC:

21045

AN:

59830

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.511

Heterozygous variant carriers

16083

32167

48250

64334

80417

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

12742

25484

38226

50968

63710

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.294

AC:

44679

AN:

152084

Hom.:

8116

Cov.:

AF XY:

0.297

AC XY:

22060

AN XY:

74344

show subpopulations

African (AFR)

AF:

0.0733

AC:

3043

AN:

41512

American (AMR)

AF:

0.355

AC:

5415

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.353

AC:

1224

AN:

3466

East Asian (EAS)

AF:

0.361

AC:

1866

AN:

5164

South Asian (SAS)

AF:

0.376

AC:

1812

AN:

4820

European-Finnish (FIN)

AF:

0.399

AC:

4211

AN:

10552

Middle Eastern (MID)

AF:

0.303

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.383

AC:

26033

AN:

67984

Other (OTH)

AF:

0.303

AC:

639

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1465

2929

4394

5858

7323

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

454

908

1362

1816

2270

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.343

Hom.:

2334

Bravo

AF:

0.280

Asia WGS

AF:

0.338

AC:

1174

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Agammaglobulinemia 7, autosomal recessive (1)

Immunodeficiency 36 with lymphoproliferation (1)

not specified (1)

SHORT syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.65

CADD

Benign

7.9

(source)

DANN

Benign

0.90

PhyloP100

-0.14

BranchPoint Hunter

4.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over