Genetic Variant NM_002638.4:c.100A>C (chr20-45175881-A-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_002638.4(PI3):c.100A>C(p.Thr34Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.176 in 1,613,876 control chromosomes in the GnomAD database, including 26,291 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 0.16 ( 2026 hom., cov: 32)

Exomes 𝑓: 0.18 ( 24265 hom. )

Consequence

PI3
NM_002638.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.40

Publications

37 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:

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ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (MetaRNN=0.001419872).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.18 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PI3	NM_002638.4 link	c.100A>C	p.Thr34Pro	missense_variant	Exon 2 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.100A>C	p.Thr34Pro	missense_variant	Exon 2 of 3	1	NM_002638.4	ENSP00000243924.3		P19957

Frequencies

GnomAD3 genomes

AF:

0.157

AC:

23921

AN:

152048

Hom.:

2021

Cov.:

show subpopulations

Gnomad AFR

AF:

0.124

Gnomad AMI

AF:

0.316

Gnomad AMR

AF:

0.135

Gnomad ASJ

AF:

0.205

Gnomad EAS

AF:

0.0326

Gnomad SAS

AF:

0.143

Gnomad FIN

AF:

0.193

Gnomad MID

AF:

0.231

Gnomad NFE

AF:

0.182

Gnomad OTH

AF:

0.164

GnomAD2 exomes

AF:

0.155

AC:

39041

AN:

251378

AF XY:

0.161

show subpopulations

Gnomad AFR exome

AF:

0.124

Gnomad AMR exome

AF:

0.0886

Gnomad ASJ exome

AF:

0.200

Gnomad EAS exome

AF:

0.0305

Gnomad FIN exome

AF:

0.196

Gnomad NFE exome

AF:

0.186

Gnomad OTH exome

AF:

0.168

GnomAD4 exome

AF:

0.177

AC:

259373

AN:

1461710

Hom.:

24265

Cov.:

AF XY:

0.177

AC XY:

128810

AN XY:

727160

show subpopulations

African (AFR)

AF:

0.121

AC:

4045

AN:

33480

American (AMR)

AF:

0.0931

AC:

4162

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.201

AC:

5240

AN:

26134

East Asian (EAS)

AF:

0.0199

AC:

791

AN:

39700

South Asian (SAS)

AF:

0.167

AC:

14401

AN:

86254

European-Finnish (FIN)

AF:

0.195

AC:

10392

AN:

53418

Middle Eastern (MID)

AF:

0.201

AC:

1162

AN:

5768

European-Non Finnish (NFE)

AF:

0.188

AC:

208998

AN:

1111844

Other (OTH)

AF:

0.169

AC:

10182

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

11738

23476

35214

46952

58690

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.157

AC:

23960

AN:

152166

Hom.:

2026

Cov.:

AF XY:

0.158

AC XY:

11740

AN XY:

74398

show subpopulations

African (AFR)

AF:

0.124

AC:

5162

AN:

41524

American (AMR)

AF:

0.135

AC:

2059

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.205

AC:

712

AN:

3472

East Asian (EAS)

AF:

0.0324

AC:

168

AN:

5180

South Asian (SAS)

AF:

0.144

AC:

696

AN:

4818

European-Finnish (FIN)

AF:

0.193

AC:

2048

AN:

10586

Middle Eastern (MID)

AF:

0.241

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.182

AC:

12402

AN:

67982

Other (OTH)

AF:

0.168

AC:

354

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1009

2018

3026

4035

5044

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.175

Hom.:

11354

Bravo

AF:

0.151

TwinsUK

AF:

0.193

AC:

714

ALSPAC

AF:

0.202

AC:

777

ESP6500AA

AF:

0.127

AC:

560

ESP6500EA

AF:

0.184

AC:

1581

ExAC

AF:

0.156

AC:

18922

Asia WGS

AF:

0.0930

AC:

322

AN:

3478

EpiCase

AF:

0.183

EpiControl

AF:

0.188

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.060

BayesDel_addAF

Benign

-0.81

BayesDel_noAF

Benign

-0.79

CADD

Benign

0.018

(source)

DANN

Benign

0.58

DEOGEN2

Benign

0.047

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.012

LIST_S2

Benign

0.43

MetaRNN

Benign

0.0014

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.73

PhyloP100

-2.4

PrimateAI

Benign

0.28

PROVEAN

Benign

-0.28

REVEL

Benign

0.030

Sift

Benign

0.46

Sift4G

Benign

0.36

Polyphen

0.018

Vest4

0.033

MPC

0.22

ClinPred

0.0070

GERP RS

-5.1

Varity_R

0.13

gMVP

0.20

Mutation Taster

=98/2

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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NM_002638.4:c.100A>C

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