Genetic Variant KLK3:c.630+453C>T (chr19-50859048-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 NM_001648.2(KLK3):c.630+453C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.296 in 227,216 control chromosomes in the GnomAD database, including 11,669 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 0.28 ( 7218 hom., cov: 29)

Exomes 𝑓: 0.32 ( 4451 hom. )

Consequence

KLK3
NM_001648.2 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.89

Publications

3 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=-0.9).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.414 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein
KLK3	NM_001648.2 link	c.630+453C>T	intron_variant	Intron 4 of 4	ENST00000326003.7	NP_001639.1
KLK3	NM_001030047.1 link	c.630+453C>T	intron_variant	Intron 4 of 4		NP_001025218.1
KLK3	NM_001030048.1 link	c.501+453C>T	intron_variant	Intron 4 of 4		NP_001025219.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KLK3	ENST00000326003.7 link	c.630+453C>T		intron_variant	Intron 4 of 4	1	NM_001648.2	ENSP00000314151.1

Frequencies

GnomAD3 genomes

AF:

0.281

AC:

42536

AN:

151372

Hom.:

7214

Cov.:

show subpopulations

Gnomad AFR

AF:

0.112

Gnomad AMI

AF:

0.249

Gnomad AMR

AF:

0.371

Gnomad ASJ

AF:

0.251

Gnomad EAS

AF:

0.429

Gnomad SAS

AF:

0.182

Gnomad FIN

AF:

0.460

Gnomad MID

AF:

0.220

Gnomad NFE

AF:

0.335

Gnomad OTH

AF:

0.267

GnomAD4 exome

AF:

0.325

AC:

24599

AN:

75726

Hom.:

4451

AF XY:

0.322

AC XY:

12381

AN XY:

38498

show subpopulations

African (AFR)

AF:

0.103

AC:

309

AN:

2998

American (AMR)

AF:

0.387

AC:

1569

AN:

4058

Ashkenazi Jewish (ASJ)

AF:

0.234

AC:

627

AN:

2680

East Asian (EAS)

AF:

0.432

AC:

2436

AN:

5642

South Asian (SAS)

AF:

0.173

AC:

512

AN:

2960

European-Finnish (FIN)

AF:

0.478

AC:

1811

AN:

3786

Middle Eastern (MID)

AF:

0.192

AC:

AN:

334

European-Non Finnish (NFE)

AF:

0.326

AC:

15812

AN:

48450

Other (OTH)

AF:

0.303

AC:

1459

AN:

4818

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.510

Heterozygous variant carriers

790

1580

2370

3160

3950

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

152

304

456

608

760

<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:

0.281

AC:

42555

AN:

151490

Hom.:

7218

Cov.:

AF XY:

0.285

AC XY:

21072

AN XY:

73994

show subpopulations

African (AFR)

AF:

0.112

AC:

4610

AN:

41324

American (AMR)

AF:

0.371

AC:

5661

AN:

15254

Ashkenazi Jewish (ASJ)

AF:

0.251

AC:

869

AN:

3464

East Asian (EAS)

AF:

0.429

AC:

2175

AN:

5074

South Asian (SAS)

AF:

0.181

AC:

867

AN:

4778

European-Finnish (FIN)

AF:

0.460

AC:

4837

AN:

10518

Middle Eastern (MID)

AF:

0.209

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.335

AC:

22675

AN:

67778

Other (OTH)

AF:

0.273

AC:

574

AN:

2100

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

1403

2807

4210

5614

7017

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

430

860

1290

1720

2150

<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:

0.273

Hom.:

1254

Bravo

AF:

0.267

Asia WGS

AF:

0.302

AC:

1048

AN:

3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

0.19

(source)

DANN

Benign

0.56

PhyloP100

-2.9

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