dbSNP rs41282752: PI3:p.Ala15Thr (chr20-45174965-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_002638.4(PI3):c.43G>A(p.Ala15Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0337 in 1,612,976 control chromosomes in the GnomAD database, including 1,132 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 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 0.029 ( 107 hom., cov: 32)

Exomes 𝑓: 0.034 ( 1025 hom. )

Consequence

PI3
NM_002638.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.123

Publications

13 publications found

Variant links:

Genes affected

PI3 (HGNC:8947): (peptidase inhibitor 3) This gene encodes an elastase-specific inhibitor that functions as an antimicrobial peptide against Gram-positive and Gram-negative bacteria, and fungal pathogens. The protein contains a WAP-type four-disulfide core (WFDC) domain, and is thus a member of the WFDC domain family. Most WFDC gene members are localized to chromosome 20q12-q13 in two clusters: centromeric and telomeric. This gene belongs to the centromeric cluster. Expression of this gene is upgulated by bacterial lipopolysaccharides and cytokines. [provided by RefSeq, Oct 2014]

PI3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0021921098).

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0285 (4345/152274) while in subpopulation NFE AF = 0.0418 (2845/68020). AF 95% confidence interval is 0.0405. There are 107 homozygotes in GnomAd4. There are 2054 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 107 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PI3	NM_002638.4 link	c.43G>A	p.Ala15Thr	missense_variant	Exon 1 of 3	ENST00000243924.4	NP_002629.1	P19957

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PI3	ENST00000243924.4 link	c.43G>A	p.Ala15Thr	missense_variant	Exon 1 of 3	1	NM_002638.4	ENSP00000243924.3		P19957

Frequencies

GnomAD3 genomes

AF:

0.0286

AC:

4345

AN:

152156

Hom.:

107

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00623

Gnomad AMI

AF:

0.0440

Gnomad AMR

AF:

0.0243

Gnomad ASJ

AF:

0.0861

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00559

Gnomad FIN

AF:

0.0408

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.0418

Gnomad OTH

AF:

0.0306

GnomAD2 exomes

AF:

0.0291

AC:

7290

AN:

250164

AF XY:

0.0291

show subpopulations

Gnomad AFR exome

AF:

0.00506

Gnomad AMR exome

AF:

0.0179

Gnomad ASJ exome

AF:

0.0776

Gnomad EAS exome

AF:

0.000219

Gnomad FIN exome

AF:

0.0429

Gnomad NFE exome

AF:

0.0401

Gnomad OTH exome

AF:

0.0316

GnomAD4 exome

AF:

0.0342

AC:

49997

AN:

1460702

Hom.:

1025

Cov.:

AF XY:

0.0337

AC XY:

24490

AN XY:

726602

show subpopulations

African (AFR)

AF:

0.00479

AC:

160

AN:

33420

American (AMR)

AF:

0.0172

AC:

769

AN:

44624

Ashkenazi Jewish (ASJ)

AF:

0.0837

AC:

2184

AN:

26098

East Asian (EAS)

AF:

0.0000505

AC:

AN:

39600

South Asian (SAS)

AF:

0.00540

AC:

465

AN:

86182

European-Finnish (FIN)

AF:

0.0415

AC:

2218

AN:

53410

Middle Eastern (MID)

AF:

0.0177

AC:

102

AN:

5762

European-Non Finnish (NFE)

AF:

0.0380

AC:

42266

AN:

1111270

Other (OTH)

AF:

0.0303

AC:

1831

AN:

60336

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

2352

4705

7057

9410

11762

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1498

2996

4494

5992

7490

<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:

0.0285

AC:

4345

AN:

152274

Hom.:

107

Cov.:

AF XY:

0.0276

AC XY:

2054

AN XY:

74448

show subpopulations

African (AFR)

AF:

0.00621

AC:

258

AN:

41544

American (AMR)

AF:

0.0242

AC:

371

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.0861

AC:

299

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00559

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.0408

AC:

433

AN:

10608

Middle Eastern (MID)

AF:

0.0272

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0418

AC:

2845

AN:

68020

Other (OTH)

AF:

0.0303

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

220

441

661

882

1102

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

104

156

208

260

<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:

0.0377

Hom.:

367

Bravo

AF:

0.0256

TwinsUK

AF:

0.0421

AC:

156

ALSPAC

AF:

0.0309

AC:

119

ESP6500AA

AF:

0.00681

AC:

ESP6500EA

AF:

0.0405

AC:

348

ExAC

AF:

0.0290

AC:

3521

Asia WGS

AF:

0.00346

AC:

AN:

3478

EpiCase

AF:

0.0406

EpiControl

AF:

0.0377

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.097

BayesDel_addAF

Benign

-0.73

BayesDel_noAF

Benign

-0.79

CADD

Benign

6.6

(source)

DANN

Benign

0.91

DEOGEN2

Benign

0.081

Eigen

Benign

-0.98

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.039

LIST_S2

Benign

0.52

MetaRNN

Benign

0.0022

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.69

PhyloP100

-0.12

PrimateAI

Benign

0.27

PROVEAN

Benign

-0.21

REVEL

Benign

0.011

Sift

Benign

0.19

Sift4G

Uncertain

0.031

Polyphen

0.47

Vest4

0.042

MPC

0.17

ClinPred

0.0015

GERP RS

1.9

PromoterAI

-0.11

Neutral

(source)

Varity_R

0.030

gMVP

0.25

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over