19-50856241-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001648.2(KLK3):c.48T>C(p.Gly16=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.406 in 1,606,658 control chromosomes in the GnomAD database, including 136,964 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.37 (11196 hom., cov: 31)
  • Exomes 𝑓: 0.41 (125768 hom.)
• Consequence: KLK3 NM_001648.2 splice_region, synonymous
• Scores: Splicing: ADA: 0.0005339
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.529

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_addAF=-0.922523).
• BP6: Variant 19-50856241-T-C is Benign according to our data. Variant chr19-50856241-T-C is described in ClinVar as [Benign]. Clinvar id is 3059788.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.49 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KLK3	NM_001648.2	c.48T>C	p.Gly16=	splice_region_variant, synonymous_variant	2/5	ENST00000326003.7
KLK3	NM_001030047.1	c.48T>C	p.Gly16=	splice_region_variant, synonymous_variant	2/5
KLK3	NM_001030048.1	c.48T>C	p.Gly16=	splice_region_variant, synonymous_variant	2/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KLK3	ENST00000326003.7	c.48T>C	p.Gly16=	splice_region_variant, synonymous_variant	2/5	1	NM_001648.2	P1

Frequencies

GnomAD3 genomes AF: 0.370 AC: 56103 AN: 151696 Hom.: 11191 Cov.: 31

Gnomad AFR AF: 0.228

Gnomad AMI AF: 0.444

Gnomad AMR AF: 0.456

Gnomad ASJ AF: 0.380

Gnomad EAS AF: 0.507

Gnomad SAS AF: 0.226

Gnomad FIN AF: 0.460

Gnomad MID AF: 0.326

Gnomad NFE AF: 0.421

Gnomad OTH AF: 0.373

GnomAD3 exomes AF: 0.403 AC: 100569 AN: 249588 Hom.: 21569 AF XY: 0.391 AC XY: 52809 AN XY: 134912

Gnomad AFR exome AF: 0.227

Gnomad AMR exome AF: 0.523

Gnomad ASJ exome AF: 0.384

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: 0.399

GnomAD4 exome AF: 0.409 AC: 595567 AN: 1454844 Hom.: 125768 Cov.: 35 AF XY: 0.404 AC XY: 292654 AN XY: 724004

Gnomad4 AFR exome AF: 0.217

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: 0.370 AC: 56128 AN: 151814 Hom.: 11196 Cov.: 31 AF XY: 0.370 AC XY: 27416 AN XY: 74196

Gnomad4 AFR AF: 0.228

Gnomad4 AMR AF: 0.456

Gnomad4 ASJ AF: 0.380

Gnomad4 EAS AF: 0.506

Gnomad4 SAS AF: 0.226

Gnomad4 FIN AF: 0.460

Gnomad4 NFE AF: 0.421

Gnomad4 OTH AF: 0.379

Alfa AF: 0.395 Hom.: 10865

Bravo AF: 0.368

TwinsUK AF: 0.417 AC: 1546

ALSPAC AF: 0.417 AC: 1607

ESP6500AA AF: 0.242 AC: 1066

ESP6500EA AF: 0.417 AC: 3589

ExAC AF: 0.393 AC: 47683

Asia WGS AF: 0.363 AC: 1264 AN: 3478

EpiCase AF: 0.406

EpiControl AF: 0.406

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_addAF	Benign	-0.92	T
BayesDel_noAF	Benign	-0.95
Cadd	Benign	0.57
Dann	Benign	0.25
FATHMM_MKL	Benign	0.040	N
MutationTaster	Benign	1.0e-37	P;P;P;P
GERP RS		-1.4

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00053
dbscSNV1_RF	Benign	0.056
SpliceAI score (max)		0.26		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.26		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs11573; hg19: chr19-51359497; COSMIC: COSV58100686; COSMIC: COSV58100686;