Genetic Variant KLK3:n.944G>C (chr19-50855858-G-C) – ACMG Classification: Benign (-12 pts)

Variant summary

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

The ENST00000601349.5(KLK3):n.944G>C 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 0.847 in 171,304 control chromosomes in the GnomAD database, including 62,021 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 0.85 ( 55326 hom., cov: 31)

Exomes 𝑓: 0.83 ( 6695 hom. )

Consequence

KLK3
ENST00000601349.5 non_coding_transcript_exon

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -3.56

Publications

5 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=-1.02).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.887 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
KLK3	NM_001648.2 link	c.47-382G>C	intron_variant	Intron 1 of 4	ENST00000326003.7	NP_001639.1	P07288-1Q546G3
KLK3	NM_001030047.1 link	c.47-382G>C	intron_variant	Intron 1 of 4		NP_001025218.1	P07288-2
KLK3	NM_001030048.1 link	c.47-382G>C	intron_variant	Intron 1 of 4		NP_001025219.1	P07288-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KLK3	ENST00000326003.7 link	c.47-382G>C		intron_variant	Intron 1 of 4	1	NM_001648.2	ENSP00000314151.1		P07288-1

Frequencies

GnomAD3 genomes

AF:

0.849

AC:

129153

AN:

152036

Hom.:

55288

Cov.:

show subpopulations

Gnomad AFR

AF:

0.895

Gnomad AMI

AF:

0.856

Gnomad AMR

AF:

0.803

Gnomad ASJ

AF:

0.769

Gnomad EAS

AF:

0.593

Gnomad SAS

AF:

0.614

Gnomad FIN

AF:

0.920

Gnomad MID

AF:

0.766

Gnomad NFE

AF:

0.863

Gnomad OTH

AF:

0.824

GnomAD4 exome

AF:

0.830

AC:

15891

AN:

19150

Hom.:

6695

Cov.:

AF XY:

0.825

AC XY:

7894

AN XY:

9570

show subpopulations

African (AFR)

AF:

0.895

AC:

453

AN:

506

American (AMR)

AF:

0.779

AC:

777

AN:

998

Ashkenazi Jewish (ASJ)

AF:

0.777

AC:

491

AN:

632

East Asian (EAS)

AF:

0.580

AC:

414

AN:

714

South Asian (SAS)

AF:

0.644

AC:

551

AN:

856

European-Finnish (FIN)

AF:

0.925

AC:

940

AN:

1016

Middle Eastern (MID)

AF:

0.679

AC:

AN:

European-Non Finnish (NFE)

AF:

0.855

AC:

11230

AN:

13142

Other (OTH)

AF:

0.813

AC:

982

AN:

1208

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

124

249

373

498

622

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

144

216

288

360

<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:

0.849

AC:

129244

AN:

152154

Hom.:

55326

Cov.:

AF XY:

0.845

AC XY:

62858

AN XY:

74378

show subpopulations

African (AFR)

AF:

0.894

AC:

37115

AN:

41494

American (AMR)

AF:

0.802

AC:

12263

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.769

AC:

2661

AN:

3462

East Asian (EAS)

AF:

0.593

AC:

3061

AN:

5160

South Asian (SAS)

AF:

0.614

AC:

2953

AN:

4810

European-Finnish (FIN)

AF:

0.920

AC:

9765

AN:

10618

Middle Eastern (MID)

AF:

0.745

AC:

219

AN:

294

European-Non Finnish (NFE)

AF:

0.863

AC:

58686

AN:

68014

Other (OTH)

AF:

0.825

AC:

1740

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

957

1913

2870

3826

4783

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

880

1760

2640

3520

4400

<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:

0.856

Hom.:

3238

Bravo

AF:

0.844

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-1.0

CADD

Benign

0.079

(source)

DANN

Benign

0.53

PhyloP100

-3.6

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