Genetic Variant KLK3:n.122A>G (chr19-50857512-A-G) – 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.122A>G 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 0.943 in 155,320 control chromosomes in the GnomAD database, including 69,217 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 0.94 ( 67857 hom., cov: 31)

Exomes 𝑓: 0.93 ( 1360 hom. )

Consequence

KLK3
ENST00000601812.1 non_coding_transcript_exon

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -4.78

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=-0.99).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.973 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
KLK3	NM_001648.2 link	c.207-517A>G	intron_variant	Intron 2 of 4	ENST00000326003.7	NP_001639.1	P07288-1Q546G3
KLK3	NM_001030047.1 link	c.207-517A>G	intron_variant	Intron 2 of 4		NP_001025218.1	P07288-2
KLK3	NM_001030048.1 link	c.207-646A>G	intron_variant	Intron 2 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.207-517A>G		intron_variant	Intron 2 of 4	1	NM_001648.2	ENSP00000314151.1		P07288-1

Frequencies

GnomAD3 genomes

AF:

0.943

AC:

143415

AN:

152072

Hom.:

67802

Cov.:

show subpopulations

Gnomad AFR

AF:

0.981

Gnomad AMI

AF:

0.979

Gnomad AMR

AF:

0.858

Gnomad ASJ

AF:

0.908

Gnomad EAS

AF:

0.848

Gnomad SAS

AF:

0.858

Gnomad FIN

AF:

0.973

Gnomad MID

AF:

0.851

Gnomad NFE

AF:

0.950

Gnomad OTH

AF:

0.922

GnomAD4 exome

AF:

0.930

AC:

2911

AN:

3130

Hom.:

1360

Cov.:

AF XY:

0.928

AC XY:

1634

AN XY:

1760

show subpopulations

African (AFR)

AF:

1.00

AC:

AN:

American (AMR)

AF:

0.800

AC:

256

AN:

320

Ashkenazi Jewish (ASJ)

AF:

1.00

AC:

AN:

East Asian (EAS)

AF:

0.925

AC:

AN:

South Asian (SAS)

AF:

0.839

AC:

146

AN:

174

European-Finnish (FIN)

AF:

0.992

AC:

125

AN:

126

Middle Eastern (MID)

AF:

0.833

AC:

AN:

European-Non Finnish (NFE)

AF:

0.950

AC:

2177

AN:

2292

Other (OTH)

AF:

0.950

AC:

133

AN:

140

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

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:

0.943

AC:

143523

AN:

152190

Hom.:

67857

Cov.:

AF XY:

0.940

AC XY:

69907

AN XY:

74390

show subpopulations

African (AFR)

AF:

0.981

AC:

40761

AN:

41548

American (AMR)

AF:

0.857

AC:

13091

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.908

AC:

3154

AN:

3472

East Asian (EAS)

AF:

0.848

AC:

4350

AN:

5128

South Asian (SAS)

AF:

0.859

AC:

4127

AN:

4806

European-Finnish (FIN)

AF:

0.973

AC:

10335

AN:

10620

Middle Eastern (MID)

AF:

0.837

AC:

246

AN:

294

European-Non Finnish (NFE)

AF:

0.950

AC:

64613

AN:

68018

Other (OTH)

AF:

0.925

AC:

1953

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

417

834

1250

1667

2084

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

908

1816

2724

3632

4540

<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:

0.946

Hom.:

94009

Bravo

AF:

0.935

Asia WGS

AF:

0.867

AC:

3017

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.99

CADD

Benign

0.081

(source)

DANN

Benign

0.19

PhyloP100

-4.8

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