rs266879

Positions:

• chr19-50855382-C-G
• chr19-50855382-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001648.2(KLK3):​c.46+381C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.331 in 232,162 control chromosomes in the GnomAD database, including 13,287 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 0.33 (8560 hom., cov: 31)
  • Exomes 𝑓: 0.34 (4727 hom.)
• Consequence: KLK3 NM_001648.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.29

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.374 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KLK3	NM_001648.2	c.46+381C>G		intron_variant		ENST00000326003.7
KLK3	NM_001030047.1	c.46+381C>G		intron_variant
KLK3	NM_001030048.1	c.46+381C>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KLK3	ENST00000326003.7	c.46+381C>G		intron_variant		1	NM_001648.2	P1

Frequencies

GnomAD3 genomes AF: 0.327 AC: 49713 AN: 151908 Hom.: 8557 Cov.: 31

Gnomad AFR AF: 0.293

Gnomad AMI AF: 0.302

Gnomad AMR AF: 0.260

Gnomad ASJ AF: 0.340

Gnomad EAS AF: 0.0685

Gnomad SAS AF: 0.260

Gnomad FIN AF: 0.386

Gnomad MID AF: 0.362

Gnomad NFE AF: 0.378

Gnomad OTH AF: 0.327

GnomAD4 exome AF: 0.338 AC: 27123 AN: 80132 Hom.: 4727 Cov.: 0 AF XY: 0.334 AC XY: 13965 AN XY: 41768

Gnomad4 AFR exome AF: 0.293

Gnomad4 AMR exome AF: 0.224

Gnomad4 ASJ exome AF: 0.324

Gnomad4 EAS exome AF: 0.0734

Gnomad4 SAS exome AF: 0.278

Gnomad4 FIN exome AF: 0.385

Gnomad4 NFE exome AF: 0.381

Gnomad4 OTH exome AF: 0.349

GnomAD4 genome AF: 0.327 AC: 49740 AN: 152030 Hom.: 8560 Cov.: 31 AF XY: 0.324 AC XY: 24091 AN XY: 74316

Gnomad4 AFR AF: 0.294

Gnomad4 AMR AF: 0.260

Gnomad4 ASJ AF: 0.340

Gnomad4 EAS AF: 0.0690

Gnomad4 SAS AF: 0.261

Gnomad4 FIN AF: 0.386

Gnomad4 NFE AF: 0.378

Gnomad4 OTH AF: 0.323

Alfa AF: 0.238 Hom.: 573

Bravo AF: 0.316

Asia WGS AF: 0.151 AC: 525 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.034
DANN	Benign	0.55

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs266879; hg19: chr19-51358638;