19-50858216-C-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BA1

The NM_001648.2(KLK3):c.394C>A(p.Leu132Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0862 in 1,614,118 control chromosomes in the GnomAD database, including 6,445 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

Frequency

Genomes: 𝑓 0.098 ( 812 hom., cov: 31)

Exomes 𝑓: 0.085 ( 5633 hom. )

Consequence

KLK3
NM_001648.2 missense

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: -1.11

Publications

24 publications found

Variant links:

Genes affected

KLK3 (HGNC:6364): (kallikrein related peptidase 3) Kallikreins are a subgroup of serine proteases having diverse physiological functions. Growing evidence suggests that many kallikreins are implicated in carcinogenesis and some have potential as novel cancer and other disease biomarkers. The gene is one of the fifteen kallikrein subfamily members located in a cluster on chromosome 19. It encodes a single-chain glycoprotein, a protease which is synthesized in the epithelial cells of the prostate gland, and is present in seminal plasma. It is thought to function normally in the liquefaction of seminal coagulum, presumably by hydrolysis of the high molecular mass seminal vesicle protein. The serum level of this protein, called PSA in the clinical setting, is useful in the diagnosis and monitoring of prostatic carcinoma. Alternate splicing of this gene generates several transcript variants encoding different isoforms. [provided by RefSeq, Dec 2019]

KLK3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.003845185).

BP6

Variant 19-50858216-C-A is Benign according to our data. Variant chr19-50858216-C-A is described in ClinVar as Benign. ClinVar VariationId is 3056698.Status of the report is no_assertion_criteria_provided, 0 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.134 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
KLK3	NM_001648.2 link	c.394C>A	p.Leu132Ile	missense_variant	Exon 3 of 5	ENST00000326003.7	NP_001639.1
KLK3	NM_001030047.1 link	c.394C>A	p.Leu132Ile	missense_variant	Exon 3 of 5		NP_001025218.1
KLK3	NM_001030048.1 link	c.265C>A	p.Leu89Ile	missense_variant	Exon 3 of 5		NP_001025219.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KLK3	ENST00000326003.7 link	c.394C>A	p.Leu132Ile	missense_variant	Exon 3 of 5	1	NM_001648.2	ENSP00000314151.1

Frequencies

GnomAD3 genomes

AF:

0.0984

AC:

14968

AN:

152148

Hom.:

811

Cov.:

show subpopulations

Gnomad AFR

AF:

0.137

Gnomad AMI

AF:

0.178

Gnomad AMR

AF:

0.0916

Gnomad ASJ

AF:

0.129

Gnomad EAS

AF:

0.0708

Gnomad SAS

AF:

0.0451

Gnomad FIN

AF:

0.0390

Gnomad MID

AF:

0.111

Gnomad NFE

AF:

0.0884

Gnomad OTH

AF:

0.108

GnomAD2 exomes

AF:

0.0807

AC:

20271

AN:

251232

AF XY:

0.0789

show subpopulations

Gnomad AFR exome

AF:

0.143

Gnomad AMR exome

AF:

0.0743

Gnomad ASJ exome

AF:

0.135

Gnomad EAS exome

AF:

0.0748

Gnomad FIN exome

AF:

0.0432

Gnomad NFE exome

AF:

0.0856

Gnomad OTH exome

AF:

0.0923

GnomAD4 exome

AF:

0.0849

AC:

124156

AN:

1461852

Hom.:

5633

Cov.:

AF XY:

0.0842

AC XY:

61248

AN XY:

727232

show subpopulations

African (AFR)

AF:

0.143

AC:

4788

AN:

33480

American (AMR)

AF:

0.0738

AC:

3302

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.137

AC:

3572

AN:

26136

East Asian (EAS)

AF:

0.0698

AC:

2769

AN:

39698

South Asian (SAS)

AF:

0.0469

AC:

4045

AN:

86258

European-Finnish (FIN)

AF:

0.0427

AC:

2282

AN:

53398

Middle Eastern (MID)

AF:

0.140

AC:

806

AN:

5768

European-Non Finnish (NFE)

AF:

0.0873

AC:

97042

AN:

1111998

Other (OTH)

AF:

0.0919

AC:

5550

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

7266

14532

21799

29065

36331

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3646

7292

10938

14584

18230

<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:

0.0984

AC:

14983

AN:

152266

Hom.:

812

Cov.:

AF XY:

0.0953

AC XY:

7094

AN XY:

74454

show subpopulations

African (AFR)

AF:

0.137

AC:

5706

AN:

41526

American (AMR)

AF:

0.0913

AC:

1398

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.129

AC:

449

AN:

3472

East Asian (EAS)

AF:

0.0710

AC:

368

AN:

5184

South Asian (SAS)

AF:

0.0449

AC:

217

AN:

4830

European-Finnish (FIN)

AF:

0.0390

AC:

414

AN:

10618

Middle Eastern (MID)

AF:

0.105

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0884

AC:

6012

AN:

68012

Other (OTH)

AF:

0.107

AC:

226

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

673

1346

2019

2692

3365

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

162

324

486

648

810

<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:

0.0913

Hom.:

2408

Bravo

AF:

0.106

TwinsUK

AF:

0.0787

AC:

292

ALSPAC

AF:

0.0874

AC:

337

ESP6500AA

AF:

0.144

AC:

634

ESP6500EA

AF:

0.0864

AC:

743

ExAC

AF:

0.0816

AC:

9902

Asia WGS

AF:

0.0610

AC:

211

AN:

3478

EpiCase

AF:

0.0963

EpiControl

AF:

0.0993

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

KLK3-related disorder

Benign:1

Dec 02, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.74

BayesDel_noAF

Benign

-0.72

CADD

Benign

0.074

(source)

DANN

Benign

0.086

DEOGEN2

Benign

0.20

.;T;T;T;.;.;.

Eigen

Benign

-1.9

Eigen_PC

Benign

-2.0

FATHMM_MKL

Benign

0.0024

LIST_S2

Benign

0.15

T;T;T;T;T;T;T

MetaRNN

Benign

0.0038

T;T;T;T;T;T;T

MetaSVM

Benign

-0.92

MutationAssessor

Benign

0.63

.;N;.;.;N;.;N

PhyloP100

-1.1

PrimateAI

Benign

0.38

PROVEAN

Benign

0.79

.;N;.;.;.;.;N

REVEL

Benign

0.016

Sift

Benign

1.0

.;T;.;.;.;.;T

Sift4G

Benign

1.0

T;T;T;T;T;T;T

Vest4

0.056, 0.12, 0.035, 0.091

MPC

0.083

ClinPred

0.0017

GERP RS

-3.7

Varity_R

0.098

gMVP

0.20

Mutation Taster

=98/2

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over