19-50856287-G-A

Position:

chr19-50856287-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001648.2(KLK3):c.94G>A(p.Glu32Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00212 in 1,613,256 control chromosomes in the GnomAD database, including 94 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.0036 ( 16 hom., cov: 31)

Exomes 𝑓: 0.0020 ( 78 hom. )

Consequence

KLK3
NM_001648.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -3.38

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 made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.004591286).

BP6

Variant 19-50856287-G-A is Benign according to our data. Variant chr19-50856287-G-A is described in ClinVar as [Benign]. Clinvar id is 784838.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0525 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KLK3	NM_001648.2 link	c.94G>A	p.Glu32Lys	missense_variant	2/5	ENST00000326003.7	NP_001639.1	P07288-1Q546G3
KLK3	NM_001030047.1 link	c.94G>A	p.Glu32Lys	missense_variant	2/5		NP_001025218.1	P07288-2
KLK3	NM_001030048.1 link	c.94G>A	p.Glu32Lys	missense_variant	2/5		NP_001025219.1	P07288-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KLK3	ENST00000326003.7 link	c.94G>A	p.Glu32Lys	missense_variant	2/5	1	NM_001648.2	ENSP00000314151.1		P07288-1

Frequencies

GnomAD3 genomes

AF:

0.00352

AC:

536

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000603

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0302

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00695

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00478

GnomAD3 exomes

AF:

0.00816

AC:

2050

AN:

251328

Hom.:

AF XY:

0.00628

AC XY:

853

AN XY:

135836

show subpopulations

Gnomad AFR exome

AF:

0.000677

Gnomad AMR exome

AF:

0.0550

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00533

Gnomad SAS exome

AF:

0.0000980

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000528

Gnomad OTH exome

AF:

0.00522

GnomAD4 exome

AF:

0.00197

AC:

2877

AN:

1460948

Hom.:

Cov.:

AF XY:

0.00172

AC XY:

1248

AN XY:

726806

show subpopulations

Gnomad4 AFR exome

AF:

0.000389

Gnomad4 AMR exome

AF:

0.0543

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00645

Gnomad4 SAS exome

AF:

0.0000928

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000468

Gnomad4 OTH exome

AF:

0.00197

GnomAD4 genome

AF:

0.00357

AC:

543

AN:

152308

Hom.:

Cov.:

AF XY:

0.00385

AC XY:

287

AN XY:

74464

show subpopulations

Gnomad4 AFR

AF:

0.000601

Gnomad4 AMR

AF:

0.0306

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00697

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00473

Alfa

AF:

0.000482

Hom.:

Bravo

AF:

0.00617

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00599

AC:

727

Asia WGS

AF:

0.00404

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 22, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.099

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.32

CADD

Benign

0.24

DANN

Uncertain

0.99

DEOGEN2

Benign

0.32

T;.;T;.;.;.

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.013

LIST_S2

Benign

0.049

T;T;T;T;T;T

MetaRNN

Benign

0.0046

T;T;T;T;T;T

MetaSVM

Benign

-0.57

MutationAssessor

Benign

-0.15

N;.;.;N;N;N

PrimateAI

Benign

0.28

PROVEAN

Uncertain

-2.6

D;.;.;.;.;D

REVEL

Uncertain

0.40

Sift

Benign

0.23

T;.;.;.;.;T

Sift4G

Benign

0.65

T;T;T;T;T;T

Polyphen

0.92

.;P;.;.;.;.

Vest4

0.16

MVP

0.77

MPC

0.40

ClinPred

0.054

GERP RS

-4.2

Varity_R

0.21

gMVP

0.29

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over