19-50858059-C-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BA1

The NM_001648.2(KLK3):c.237C>T(p.Ser79=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.119 in 1,613,068 control chromosomes in the GnomAD database, including 11,850 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.11 (868 hom., cov: 31)
  • Exomes 𝑓: 0.12 (10982 hom.)
• Consequence: KLK3 NM_001648.2 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.42

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 -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.57).
• BP6: Variant 19-50858059-C-T is Benign according to our data. Variant chr19-50858059-C-T is described in ClinVar as [Benign]. Clinvar id is 3057076.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=2.42 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.125 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KLK3	NM_001648.2	c.237C>T	p.Ser79=	synonymous_variant	3/5	ENST00000326003.7
KLK3	NM_001030047.1	c.237C>T	p.Ser79=	synonymous_variant	3/5
KLK3	NM_001030048.1	c.207-99C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KLK3	ENST00000326003.7	c.237C>T	p.Ser79=	synonymous_variant	3/5	1	NM_001648.2	P1

Frequencies

GnomAD3 genomes AF: 0.106 AC: 16058 AN: 152088 Hom.: 869 Cov.: 31

Gnomad AFR AF: 0.0789

Gnomad AMI AF: 0.179

Gnomad AMR AF: 0.103

Gnomad ASJ AF: 0.191

Gnomad EAS AF: 0.0717

Gnomad SAS AF: 0.0841

Gnomad FIN AF: 0.0634

Gnomad MID AF: 0.146

Gnomad NFE AF: 0.127

Gnomad OTH AF: 0.127

GnomAD3 exomes AF: 0.106 AC: 26495 AN: 250016 Hom.: 1535 AF XY: 0.108 AC XY: 14582 AN XY: 135150

Gnomad AFR exome AF: 0.0778

Gnomad AMR exome AF: 0.0844

Gnomad ASJ exome AF: 0.193

Gnomad EAS exome AF: 0.0748

Gnomad SAS exome AF: 0.0852

Gnomad FIN exome AF: 0.0657

Gnomad NFE exome AF: 0.126

Gnomad OTH exome AF: 0.128

GnomAD4 exome AF: 0.120 AC: 175196 AN: 1460862 Hom.: 10982 Cov.: 31 AF XY: 0.120 AC XY: 87060 AN XY: 726750

Gnomad4 AFR exome AF: 0.0777

Gnomad4 AMR exome AF: 0.0840

Gnomad4 ASJ exome AF: 0.196

Gnomad4 EAS exome AF: 0.0700

Gnomad4 SAS exome AF: 0.0866

Gnomad4 FIN exome AF: 0.0666

Gnomad4 NFE exome AF: 0.127

Gnomad4 OTH exome AF: 0.122

GnomAD4 genome AF: 0.106 AC: 16061 AN: 152206 Hom.: 868 Cov.: 31 AF XY: 0.103 AC XY: 7638 AN XY: 74412

Gnomad4 AFR AF: 0.0787

Gnomad4 AMR AF: 0.103

Gnomad4 ASJ AF: 0.191

Gnomad4 EAS AF: 0.0718

Gnomad4 SAS AF: 0.0850

Gnomad4 FIN AF: 0.0634

Gnomad4 NFE AF: 0.127

Gnomad4 OTH AF: 0.126

Alfa AF: 0.123 Hom.: 1836

Bravo AF: 0.108

Asia WGS AF: 0.0690 AC: 241 AN: 3478

EpiCase AF: 0.133

EpiControl AF: 0.138

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

KLK3-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 12, 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
BayesDel_noAF	Benign	-0.57
Cadd	Benign	4.7
Dann	Benign	0.46

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs12946; hg19: chr19-51361315; COSMIC: COSV58101910; COSMIC: COSV58101910;