chr19-50858216-C-A

Position:

• chr19-50858216-C-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_001648.2(KLK3):​c.394C>A​(p.Leu132Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0862 in 1,614,118 control chromosomes in the GnomAD database, including 6,445 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.098 (812 hom., cov: 31)
  • Exomes 𝑓: 0.085 (5633 hom.)
• Consequence: KLK3 NM_001648.2 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: -1.11

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]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003845185).
• BP6: Variant 19-50858216-C-A is Benign according to our data. Variant chr19-50858216-C-A is described in ClinVar as [Benign]. Clinvar id is 3056698.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.134 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KLK3	NM_001648.2	c.394C>A	p.Leu132Ile	missense_variant	3/5	ENST00000326003.7	NP_001639.1
KLK3	NM_001030047.1	c.394C>A	p.Leu132Ile	missense_variant	3/5		NP_001025218.1
KLK3	NM_001030048.1	c.265C>A	p.Leu89Ile	missense_variant	3/5		NP_001025219.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KLK3	ENST00000326003.7	c.394C>A	p.Leu132Ile	missense_variant	3/5	1	NM_001648.2	ENSP00000314151	P1

Frequencies

GnomAD3 genomes AF: 0.0984 AC: 14968 AN: 152148 Hom.: 811 Cov.: 31

Gnomad AFR AF: 0.137

Gnomad AMI AF: 0.178

Gnomad AMR AF: 0.0916

Gnomad ASJ AF: 0.129

Gnomad EAS AF: 0.0708

Gnomad SAS AF: 0.0451

Gnomad FIN AF: 0.0390

Gnomad MID AF: 0.111

Gnomad NFE AF: 0.0884

Gnomad OTH AF: 0.108

GnomAD3 exomes AF: 0.0807 AC: 20271 AN: 251232 Hom.: 947 AF XY: 0.0789 AC XY: 10713 AN XY: 135800

Gnomad AFR exome AF: 0.143

Gnomad AMR exome AF: 0.0743

Gnomad ASJ exome AF: 0.135

Gnomad EAS exome AF: 0.0748

Gnomad SAS exome AF: 0.0468

Gnomad FIN exome AF: 0.0432

Gnomad NFE exome AF: 0.0856

Gnomad OTH exome AF: 0.0923

GnomAD4 exome AF: 0.0849 AC: 124156 AN: 1461852 Hom.: 5633 Cov.: 32 AF XY: 0.0842 AC XY: 61248 AN XY: 727232

Gnomad4 AFR exome AF: 0.143

Gnomad4 AMR exome AF: 0.0738

Gnomad4 ASJ exome AF: 0.137

Gnomad4 EAS exome AF: 0.0698

Gnomad4 SAS exome AF: 0.0469

Gnomad4 FIN exome AF: 0.0427

Gnomad4 NFE exome AF: 0.0873

Gnomad4 OTH exome AF: 0.0919

GnomAD4 genome AF: 0.0984 AC: 14983 AN: 152266 Hom.: 812 Cov.: 31 AF XY: 0.0953 AC XY: 7094 AN XY: 74454

Gnomad4 AFR AF: 0.137

Gnomad4 AMR AF: 0.0913

Gnomad4 ASJ AF: 0.129

Gnomad4 EAS AF: 0.0710

Gnomad4 SAS AF: 0.0449

Gnomad4 FIN AF: 0.0390

Gnomad4 NFE AF: 0.0884

Gnomad4 OTH AF: 0.107

Alfa AF: 0.0931 Hom.: 1174

Bravo AF: 0.106

TwinsUK AF: 0.0787 AC: 292

ALSPAC AF: 0.0874 AC: 337

ESP6500AA AF: 0.144 AC: 634

ESP6500EA AF: 0.0864 AC: 743

ExAC AF: 0.0816 AC: 9902

Asia WGS AF: 0.0610 AC: 211 AN: 3478

EpiCase AF: 0.0963

EpiControl AF: 0.0993

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

KLK3-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 02, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.74	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	0.074
DANN	Benign	0.086
DEOGEN2	Benign	0.20	.;T;T;T;.;.;.
Eigen	Benign	-1.9
Eigen_PC	Benign	-2.0
FATHMM_MKL	Benign	0.0024	N
LIST_S2	Benign	0.15	T;T;T;T;T;T;T
MetaRNN	Benign	0.0038	T;T;T;T;T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.63	.;N;.;.;N;.;N
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.38	T
PROVEAN	Benign	0.79	.;N;.;.;.;.;N
REVEL	Benign	0.016
Sift	Benign	1.0	.;T;.;.;.;.;T
Sift4G	Benign	1.0	T;T;T;T;T;T;T
Vest4		0.056, 0.12, 0.035, 0.091
MPC		0.083
ClinPred		0.0017	T
GERP RS		-3.7
Varity_R		0.098
gMVP		0.20

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs2003783; hg19: chr19-51361472; COSMIC: COSV58099647; COSMIC: COSV58099647;