NM_002638.4:c.50C>T

Variant names:

• chr20-45174972-C-T
• rs17333103
• NM_002638.4:c.50C>T

Variant summary

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

The NM_002638.4(PI3):​c.50C>T​(p.Thr17Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.168 in 1,612,016 control chromosomes in the GnomAD database, including 24,254 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 0.15 (1920 hom., cov: 32)
  • Exomes 𝑓: 0.17 (22334 hom.)
• Consequence: PI3 NM_002638.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.09
• Publications: 25 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=0.002602756).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.172 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PI3	NM_002638.4	c.50C>T	p.Thr17Met	missense_variant	Exon 1 of 3	ENST00000243924.4	NP_002629.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PI3	ENST00000243924.4	c.50C>T	p.Thr17Met	missense_variant	Exon 1 of 3	1	NM_002638.4	ENSP00000243924.3

Frequencies

GnomAD3 genomes AF: 0.153 AC: 23250 AN: 152020 Hom.: 1915 Cov.: 32

Gnomad AFR AF: 0.123

Gnomad AMI AF: 0.312

Gnomad AMR AF: 0.130

Gnomad ASJ AF: 0.210

Gnomad EAS AF: 0.0339

Gnomad SAS AF: 0.145

Gnomad FIN AF: 0.191

Gnomad MID AF: 0.231

Gnomad NFE AF: 0.175

Gnomad OTH AF: 0.163

GnomAD2 exomes AF: 0.151 AC: 37608 AN: 249830 AF XY: 0.156

Gnomad AFR exome AF: 0.122

Gnomad AMR exome AF: 0.0847

Gnomad ASJ exome AF: 0.205

Gnomad EAS exome AF: 0.0307

Gnomad FIN exome AF: 0.193

Gnomad NFE exome AF: 0.177

Gnomad OTH exome AF: 0.161

GnomAD4 exome AF: 0.170 AC: 248284 AN: 1459878 Hom.: 22334 Cov.: 32 AF XY: 0.170 AC XY: 123567 AN XY: 726234

African (AFR) AF: 0.119 AC: 3976 AN: 33392

American (AMR) AF: 0.0893 AC: 3984 AN: 44600

Ashkenazi Jewish (ASJ) AF: 0.206 AC: 5363 AN: 26080

East Asian (EAS) AF: 0.0214 AC: 845 AN: 39574

South Asian (SAS) AF: 0.167 AC: 14408 AN: 86054

European-Finnish (FIN) AF: 0.191 AC: 10188 AN: 53388

Middle Eastern (MID) AF: 0.201 AC: 1160 AN: 5758

European-Non Finnish (NFE) AF: 0.179 AC: 198509 AN: 1110722

Other (OTH) AF: 0.163 AC: 9851 AN: 60310

GnomAD4 genome AF: 0.153 AC: 23289 AN: 152138 Hom.: 1920 Cov.: 32 AF XY: 0.154 AC XY: 11457 AN XY: 74372

African (AFR) AF: 0.123 AC: 5097 AN: 41508

American (AMR) AF: 0.130 AC: 1987 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.210 AC: 729 AN: 3470

East Asian (EAS) AF: 0.0340 AC: 176 AN: 5184

South Asian (SAS) AF: 0.147 AC: 705 AN: 4812

European-Finnish (FIN) AF: 0.191 AC: 2020 AN: 10574

Middle Eastern (MID) AF: 0.241 AC: 71 AN: 294

European-Non Finnish (NFE) AF: 0.175 AC: 11870 AN: 67988

Other (OTH) AF: 0.166 AC: 350 AN: 2108

Alfa AF: 0.166 Hom.: 8124

Bravo AF: 0.147

TwinsUK AF: 0.187 AC: 693

ALSPAC AF: 0.190 AC: 732

ESP6500AA AF: 0.126 AC: 554

ESP6500EA AF: 0.175 AC: 1508

ExAC AF: 0.151 AC: 18397

Asia WGS AF: 0.0930 AC: 322 AN: 3478

EpiCase AF: 0.176

EpiControl AF: 0.181

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.83	T
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.15
DANN	Benign	0.68
DEOGEN2	Benign	0.082	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.014	N
LIST_S2	Benign	0.39	T
MetaRNN	Benign	0.0026	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.26	N
PhyloP100		-2.1
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.93	N
REVEL	Benign	0.010
Sift	Benign	0.28	T
Sift4G	Benign	0.22	T
Polyphen		0.085	B
Vest4		0.034
MPC		0.17
ClinPred		0.00030	T
GERP RS		-5.8
PromoterAI		-0.11	Neutral
Varity_R		0.017
gMVP		0.21
Mutation Taster		=100/0	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: rs17333103; hg19: chr20-43803613; COSMIC: COSV54783425;