19-50857512-A-G

Variant summary

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

The NM_001648.2(KLK3):c.207-517A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.943 in 155,320 control chromosomes in the GnomAD database, including 69,217 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 0.94 (67857 hom., cov: 31)
  • Exomes 𝑓: 0.93 (1360 hom.)
• Consequence: KLK3 NM_001648.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -4.78

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=-0.99).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.973 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KLK3	NM_001648.2	c.207-517A>G		intron_variant		ENST00000326003.7
KLK3	NM_001030047.1	c.207-517A>G		intron_variant
KLK3	NM_001030048.1	c.207-646A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KLK3	ENST00000326003.7	c.207-517A>G		intron_variant		1	NM_001648.2	P1

Frequencies

GnomAD3 genomes AF: 0.943 AC: 143415 AN: 152072 Hom.: 67802 Cov.: 31

Gnomad AFR AF: 0.981

Gnomad AMI AF: 0.979

Gnomad AMR AF: 0.858

Gnomad ASJ AF: 0.908

Gnomad EAS AF: 0.848

Gnomad SAS AF: 0.858

Gnomad FIN AF: 0.973

Gnomad MID AF: 0.851

Gnomad NFE AF: 0.950

Gnomad OTH AF: 0.922

GnomAD4 exome AF: 0.930 AC: 2911 AN: 3130 Hom.: 1360 Cov.: 0 AF XY: 0.928 AC XY: 1634 AN XY: 1760

Gnomad4 AFR exome AF: 1.00

Gnomad4 AMR exome AF: 0.800

Gnomad4 ASJ exome AF: 1.00

Gnomad4 EAS exome AF: 0.925

Gnomad4 SAS exome AF: 0.839

Gnomad4 FIN exome AF: 0.992

Gnomad4 NFE exome AF: 0.950

Gnomad4 OTH exome AF: 0.950

GnomAD4 genome AF: 0.943 AC: 143523 AN: 152190 Hom.: 67857 Cov.: 31 AF XY: 0.940 AC XY: 69907 AN XY: 74390

Gnomad4 AFR AF: 0.981

Gnomad4 AMR AF: 0.857

Gnomad4 ASJ AF: 0.908

Gnomad4 EAS AF: 0.848

Gnomad4 SAS AF: 0.859

Gnomad4 FIN AF: 0.973

Gnomad4 NFE AF: 0.950

Gnomad4 OTH AF: 0.925

Alfa AF: 0.958 Hom.: 3627

Bravo AF: 0.935

Asia WGS AF: 0.867 AC: 3017 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
Cadd	Benign	0.081
Dann	Benign	0.19

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: rs266877; hg19: chr19-51360768;