Genetic Variant KLK3:n.194C>T (chr19-50857584-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The ENST00000601812.1(KLK3):n.194C>T variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0495 in 162,514 control chromosomes in the GnomAD database, including 268 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 0.049 ( 244 hom., cov: 31)

Exomes 𝑓: 0.058 ( 24 hom. )

Consequence

KLK3
ENST00000601812.1 non_coding_transcript_exon

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0340

Publications

19 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:

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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=-0.94).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0719 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein
KLK3	NM_001648.2 link	c.207-445C>T	intron_variant	Intron 2 of 4	ENST00000326003.7	NP_001639.1
KLK3	NM_001030047.1 link	c.207-445C>T	intron_variant	Intron 2 of 4		NP_001025218.1
KLK3	NM_001030048.1 link	c.207-574C>T	intron_variant	Intron 2 of 4		NP_001025219.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KLK3	ENST00000326003.7 link	c.207-445C>T		intron_variant	Intron 2 of 4	1	NM_001648.2	ENSP00000314151.1

Frequencies

GnomAD3 genomes

AF:

0.0490

AC:

7454

AN:

152154

Hom.:

245

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0126

Gnomad AMI

AF:

0.186

Gnomad AMR

AF:

0.0336

Gnomad ASJ

AF:

0.0787

Gnomad EAS

AF:

0.000963

Gnomad SAS

AF:

0.0545

Gnomad FIN

AF:

0.0546

Gnomad MID

AF:

0.0633

Gnomad NFE

AF:

0.0736

Gnomad OTH

AF:

0.0488

GnomAD4 exome

AF:

0.0578

AC:

592

AN:

10242

Hom.:

Cov.:

AF XY:

0.0563

AC XY:

308

AN XY:

5470

show subpopulations

African (AFR)

AF:

0.0125

AC:

AN:

American (AMR)

AF:

0.0344

AC:

AN:

1162

Ashkenazi Jewish (ASJ)

AF:

0.0556

AC:

AN:

144

East Asian (EAS)

AF:

0.00

AC:

AN:

260

South Asian (SAS)

AF:

0.0558

AC:

AN:

878

European-Finnish (FIN)

AF:

0.0550

AC:

AN:

400

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.0660

AC:

448

AN:

6788

Other (OTH)

AF:

0.0472

AC:

AN:

508

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.521

Heterozygous variant carriers

121

151

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<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:

0.0490

AC:

7456

AN:

152272

Hom.:

244

Cov.:

AF XY:

0.0473

AC XY:

3523

AN XY:

74454

show subpopulations

African (AFR)

AF:

0.0125

AC:

520

AN:

41554

American (AMR)

AF:

0.0336

AC:

514

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.0787

AC:

273

AN:

3468

East Asian (EAS)

AF:

0.000965

AC:

AN:

5180

South Asian (SAS)

AF:

0.0545

AC:

263

AN:

4822

European-Finnish (FIN)

AF:

0.0546

AC:

580

AN:

10616

Middle Eastern (MID)

AF:

0.0680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0736

AC:

5009

AN:

68012

Other (OTH)

AF:

0.0483

AC:

102

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.511

Heterozygous variant carriers

378

755

1133

1510

1888

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

180

270

360

450

<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:

0.0655

Hom.:

721

Bravo

AF:

0.0471

Asia WGS

AF:

0.0150

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.94

CADD

Benign

6.1

(source)

DANN

Benign

0.54

PhyloP100

-0.034

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over