19-50856247-A-G

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.54A>G(p.Ala18=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.406 in 1,608,168 control chromosomes in the GnomAD database, including 137,079 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.37 (11211 hom., cov: 31)
  • Exomes 𝑓: 0.41 (125868 hom.)
• Consequence: KLK3 NM_001648.2 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.44

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=-1.06).
• BP6: Variant 19-50856247-A-G is Benign according to our data. Variant chr19-50856247-A-G is described in ClinVar as [Benign]. Clinvar id is 3060459.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-2.44 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.489 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KLK3	NM_001648.2	c.54A>G	p.Ala18=	synonymous_variant	2/5	ENST00000326003.7
KLK3	NM_001030047.1	c.54A>G	p.Ala18=	synonymous_variant	2/5
KLK3	NM_001030048.1	c.54A>G	p.Ala18=	synonymous_variant	2/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KLK3	ENST00000326003.7	c.54A>G	p.Ala18=	synonymous_variant	2/5	1	NM_001648.2	P1

Frequencies

GnomAD3 genomes AF: 0.371 AC: 56149 AN: 151488 Hom.: 11206 Cov.: 31

Gnomad AFR AF: 0.229

Gnomad AMI AF: 0.444

Gnomad AMR AF: 0.457

Gnomad ASJ AF: 0.380

Gnomad EAS AF: 0.506

Gnomad SAS AF: 0.227

Gnomad FIN AF: 0.462

Gnomad MID AF: 0.326

Gnomad NFE AF: 0.421

Gnomad OTH AF: 0.374

GnomAD3 exomes AF: 0.403 AC: 100794 AN: 250044 Hom.: 21611 AF XY: 0.392 AC XY: 52913 AN XY: 135142

Gnomad AFR exome AF: 0.229

Gnomad AMR exome AF: 0.524

Gnomad ASJ exome AF: 0.385

Gnomad EAS exome AF: 0.515

Gnomad SAS exome AF: 0.233

Gnomad FIN exome AF: 0.457

Gnomad NFE exome AF: 0.411

Gnomad OTH exome AF: 0.400

GnomAD4 exome AF: 0.410 AC: 596503 AN: 1456562 Hom.: 125868 Cov.: 36 AF XY: 0.404 AC XY: 293048 AN XY: 724746

Gnomad4 AFR exome AF: 0.218

Gnomad4 AMR exome AF: 0.511

Gnomad4 ASJ exome AF: 0.387

Gnomad4 EAS exome AF: 0.513

Gnomad4 SAS exome AF: 0.238

Gnomad4 FIN exome AF: 0.462

Gnomad4 NFE exome AF: 0.420

Gnomad4 OTH exome AF: 0.399

GnomAD4 genome AF: 0.371 AC: 56174 AN: 151606 Hom.: 11211 Cov.: 31 AF XY: 0.371 AC XY: 27443 AN XY: 74064

Gnomad4 AFR AF: 0.229

Gnomad4 AMR AF: 0.457

Gnomad4 ASJ AF: 0.380

Gnomad4 EAS AF: 0.506

Gnomad4 SAS AF: 0.227

Gnomad4 FIN AF: 0.462

Gnomad4 NFE AF: 0.422

Gnomad4 OTH AF: 0.380

Alfa AF: 0.388 Hom.: 5082

Bravo AF: 0.368

Asia WGS AF: 0.363 AC: 1263 AN: 3478

EpiCase AF: 0.407

EpiControl AF: 0.407

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

Oct 18, 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	-1.1
Cadd	Benign	0.016
Dann	Benign	0.20

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

Other links and lift over

dbSNP: rs1135766; hg19: chr19-51359503; COSMIC: COSV58100707; COSMIC: COSV58100707;