rs2664581

Variant names:

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

Variant summary

Our verdict is Benign. Variant got -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. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• 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

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

Verdict is Benign. Variant got -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	c.100A>C	p.Thr34Pro	missense_variant	Exon 2 of 3	ENST00000243924.4	NP_002629.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PI3	ENST00000243924.4	c.100A>C	p.Thr34Pro	missense_variant	Exon 2 of 3	1	NM_002638.4	ENSP00000243924.3

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

GnomAD3 exomes AF: 0.155 AC: 39041 AN: 251378 Hom.: 3526 AF XY: 0.161 AC XY: 21846 AN XY: 135860

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 SAS exome AF: 0.164

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

Gnomad4 AFR exome AF: 0.121

Gnomad4 AMR exome AF: 0.0931

Gnomad4 ASJ exome AF: 0.201

Gnomad4 EAS exome AF: 0.0199

Gnomad4 SAS exome AF: 0.167

Gnomad4 FIN exome AF: 0.195

Gnomad4 NFE exome AF: 0.188

Gnomad4 OTH exome AF: 0.169

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

Gnomad4 AFR AF: 0.124

Gnomad4 AMR AF: 0.135

Gnomad4 ASJ AF: 0.205

Gnomad4 EAS AF: 0.0324

Gnomad4 SAS AF: 0.144

Gnomad4 FIN AF: 0.193

Gnomad4 NFE AF: 0.182

Gnomad4 OTH AF: 0.168

Alfa AF: 0.179 Hom.: 6596

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	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
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

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

LitVar

Other links and lift over

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