Genetic Variant PI3:c.*270C>G (chr20-45176638-C-G) – 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.*270C>G variant causes a downstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.199 in 158,766 control chromosomes in the GnomAD database, including 3,232 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.20 ( 3115 hom., cov: 32)

Exomes 𝑓: 0.16 ( 117 hom. )

Consequence

PI3
NM_002638.4 downstream_gene

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.577

Publications

4 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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new If you want to explore the variant's impact on the transcript NM_002638.4, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.89).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.216 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.*270C>G		downstream_gene	N/A	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.*270C>G		downstream_gene	N/A	ENSP00000243924.3	P19957
	PI3	ENST00000971330.1		c.*268C>G		downstream_gene	N/A	ENSP00000641389.1

Frequencies

GnomAD3 genomes

AF:

0.201

AC:

30476

AN:

151766

Hom.:

3102

Cov.:

show subpopulations

Gnomad AFR

AF:

0.220

Gnomad AMI

AF:

0.316

Gnomad AMR

AF:

0.200

Gnomad ASJ

AF:

0.204

Gnomad EAS

AF:

0.101

Gnomad SAS

AF:

0.154

Gnomad FIN

AF:

0.235

Gnomad MID

AF:

0.244

Gnomad NFE

AF:

0.193

Gnomad OTH

AF:

0.204

GnomAD4 exome

AF:

0.163

AC:

1122

AN:

6882

Hom.:

117

AF XY:

0.168

AC XY:

621

AN XY:

3692

show subpopulations

African (AFR)

AF:

0.182

AC:

AN:

American (AMR)

AF:

0.160

AC:

206

AN:

1284

Ashkenazi Jewish (ASJ)

AF:

0.0909

AC:

AN:

East Asian (EAS)

AF:

0.103

AC:

AN:

234

South Asian (SAS)

AF:

0.160

AC:

129

AN:

804

European-Finnish (FIN)

AF:

0.200

AC:

AN:

110

Middle Eastern (MID)

AF:

0.438

AC:

AN:

European-Non Finnish (NFE)

AF:

0.167

AC:

672

AN:

4030

Other (OTH)

AF:

0.162

AC:

AN:

272

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

Heterozygous variant carriers

136

181

226

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.201

AC:

30540

AN:

151884

Hom.:

3115

Cov.:

AF XY:

0.204

AC XY:

15110

AN XY:

74216

show subpopulations

African (AFR)

AF:

0.220

AC:

9112

AN:

41424

American (AMR)

AF:

0.200

AC:

3057

AN:

15248

Ashkenazi Jewish (ASJ)

AF:

0.204

AC:

708

AN:

3472

East Asian (EAS)

AF:

0.101

AC:

522

AN:

5164

South Asian (SAS)

AF:

0.156

AC:

750

AN:

4822

European-Finnish (FIN)

AF:

0.235

AC:

2477

AN:

10530

Middle Eastern (MID)

AF:

0.255

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.193

AC:

13116

AN:

67914

Other (OTH)

AF:

0.207

AC:

435

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1245

2490

3734

4979

6224

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

320

640

960

1280

1600

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0981

Hom.:

137

Bravo

AF:

0.200

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.89

CADD

Benign

4.5

(source)

DANN

Benign

0.43

PhyloP100

0.58

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over