rs41282752

Positions:

• chr20-45174965-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The ENST00000243924.4(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. 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.

• Frequency:
  • Genomes: 𝑓 0.029 (107 hom., cov: 32)
  • Exomes 𝑓: 0.034 (1025 hom.)
• Consequence: PI3 ENST00000243924.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.123

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=0.0021921098).
• 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 107 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PI3	NM_002638.4	c.43G>A	p.Ala15Thr	missense_variant	1/3	ENST00000243924.4	NP_002629.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PI3	ENST00000243924.4	c.43G>A	p.Ala15Thr	missense_variant	1/3	1	NM_002638.4	ENSP00000243924	P1

Frequencies

GnomAD3 genomes AF: 0.0286 AC: 4345 AN: 152156 Hom.: 107 Cov.: 32

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

GnomAD3 exomes AF: 0.0291 AC: 7290 AN: 250164 Hom.: 177 AF XY: 0.0291 AC XY: 3941 AN XY: 135232

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 SAS exome AF: 0.00514

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.: 30 AF XY: 0.0337 AC XY: 24490 AN XY: 726602

Gnomad4 AFR exome AF: 0.00479

Gnomad4 AMR exome AF: 0.0172

Gnomad4 ASJ exome AF: 0.0837

Gnomad4 EAS exome AF: 0.0000505

Gnomad4 SAS exome AF: 0.00540

Gnomad4 FIN exome AF: 0.0415

Gnomad4 NFE exome AF: 0.0380

Gnomad4 OTH exome AF: 0.0303

GnomAD4 genome AF: 0.0285 AC: 4345 AN: 152274 Hom.: 107 Cov.: 32 AF XY: 0.0276 AC XY: 2054 AN XY: 74448

Gnomad4 AFR AF: 0.00621

Gnomad4 AMR AF: 0.0242

Gnomad4 ASJ AF: 0.0861

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00559

Gnomad4 FIN AF: 0.0408

Gnomad4 NFE AF: 0.0418

Gnomad4 OTH AF: 0.0303

Alfa AF: 0.0397 Hom.: 179

Bravo AF: 0.0256

TwinsUK AF: 0.0421 AC: 156

ALSPAC AF: 0.0309 AC: 119

ESP6500AA AF: 0.00681 AC: 30

ESP6500EA AF: 0.0405 AC: 348

ExAC AF: 0.0290 AC: 3521

Asia WGS AF: 0.00346 AC: 13 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	T
BayesDel_noAF	Benign	-0.79
CADD	Benign	6.6
DANN	Benign	0.91
DEOGEN2	Benign	0.081	T
Eigen	Benign	-0.98
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.039	N
LIST_S2	Benign	0.52	T
MetaRNN	Benign	0.0022	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.21	N
REVEL	Benign	0.011
Sift	Benign	0.19	T
Sift4G	Uncertain	0.031	D
Polyphen		0.47	P
Vest4		0.042
MPC		0.17
ClinPred		0.0015	T
GERP RS		1.9
Varity_R		0.030
gMVP		0.25

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: rs41282752; hg19: chr20-43803606;