rs2664581

Variant names:

• chr20-45175881-A-C
• rs2664581
• NM_002638.4:c.100A>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.40
• Publications: 37 publications found

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]

ACMG classification

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002638.4. 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
	PI3	NM_002638.4	MANE Select	c.100A>C	p.Thr34Pro	missense	Exon 2 of 3	NP_002629.1	P19957

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PI3	ENST00000243924.4	TSL:1 MANE Select	c.100A>C	p.Thr34Pro	missense	Exon 2 of 3	ENSP00000243924.3	P19957
	PI3	ENST00000971330.1		c.100A>C	p.Thr34Pro	missense	Exon 2 of 3	ENSP00000641389.1

Frequencies

GnomAD3 genomes AF: 0.157 AC: 23921 AN: 152048 Hom.: 2021 Cov.: 32

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

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.: 33 AF XY: 0.177 AC XY: 128810 AN XY: 727160

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

GnomAD4 genome AF: 0.157 AC: 23960 AN: 152166 Hom.: 2026 Cov.: 32 AF XY: 0.158 AC XY: 11740 AN XY: 74398

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: 71 AN: 294

European-Non Finnish (NFE) AF: 0.182 AC: 12402 AN: 67982

Other (OTH) AF: 0.168 AC: 354 AN: 2112

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 v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.81	T
BayesDel_noAF	Benign	-0.79
CADD	Benign	0.018
DANN	Benign	0.58
DEOGEN2	Benign	0.047	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.012	N
LIST_S2	Benign	0.43	T
MetaRNN	Benign	0.0014	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.73	N
PhyloP100		-2.4
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.28	N
REVEL	Benign	0.030
Sift	Benign	0.46	T
Sift4G	Benign	0.36	T
Polyphen		0.018	B
Vest4		0.033
MPC		0.22
ClinPred		0.0070	T
GERP RS		-5.1
Varity_R		0.13
gMVP		0.20
Mutation Taster		=98/2	polymorphism (auto)

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: rs2664581; hg19: chr20-43804522; COSMIC: COSV54782855;