rs61752561

Positions:

• chr19-50858126-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_001648.2(KLK3):​c.304G>A​(p.Asp102Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0343 in 1,614,032 control chromosomes in the GnomAD database, including 1,191 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.025 (67 hom., cov: 31)
  • Exomes 𝑓: 0.035 (1124 hom.)
• Consequence: KLK3 NM_001648.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.104

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]

KLK3 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003840983).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0247 (3759/152180) while in subpopulation NFE AF= 0.0418 (2843/68012). AF 95% confidence interval is 0.0405. There are 67 homozygotes in gnomad4. There are 1754 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 67 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KLK3	NM_001648.2	c.304G>A	p.Asp102Asn	missense_variant	3/5	ENST00000326003.7	NP_001639.1
KLK3	NM_001030047.1	c.304G>A	p.Asp102Asn	missense_variant	3/5		NP_001025218.1
KLK3	NM_001030048.1	c.207-32G>A		intron_variant			NP_001025219.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KLK3	ENST00000326003.7	c.304G>A	p.Asp102Asn	missense_variant	3/5	1	NM_001648.2	ENSP00000314151.1

Frequencies

GnomAD3 genomes AF: 0.0247 AC: 3758 AN: 152062 Hom.: 67 Cov.: 31

Gnomad AFR AF: 0.00700

Gnomad AMI AF: 0.0121

Gnomad AMR AF: 0.00990

Gnomad ASJ AF: 0.00980

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00894

Gnomad FIN AF: 0.0331

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0418

Gnomad OTH AF: 0.0158

GnomAD3 exomes AF: 0.0239 AC: 5995 AN: 251316 Hom.: 112 AF XY: 0.0245 AC XY: 3326 AN XY: 135848

Gnomad AFR exome AF: 0.00720

Gnomad AMR exome AF: 0.00616

Gnomad ASJ exome AF: 0.0100

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.0112

Gnomad FIN exome AF: 0.0322

Gnomad NFE exome AF: 0.0388

Gnomad OTH exome AF: 0.0192

GnomAD4 exome AF: 0.0353 AC: 51618 AN: 1461852 Hom.: 1124 Cov.: 31 AF XY: 0.0347 AC XY: 25243 AN XY: 727224

Gnomad4 AFR exome AF: 0.00568

Gnomad4 AMR exome AF: 0.00673

Gnomad4 ASJ exome AF: 0.0118

Gnomad4 EAS exome AF: 0.000151

Gnomad4 SAS exome AF: 0.0102

Gnomad4 FIN exome AF: 0.0341

Gnomad4 NFE exome AF: 0.0418

Gnomad4 OTH exome AF: 0.0267

GnomAD4 genome AF: 0.0247 AC: 3759 AN: 152180 Hom.: 67 Cov.: 31 AF XY: 0.0236 AC XY: 1754 AN XY: 74406

Gnomad4 AFR AF: 0.00698

Gnomad4 AMR AF: 0.00988

Gnomad4 ASJ AF: 0.00980

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00916

Gnomad4 FIN AF: 0.0331

Gnomad4 NFE AF: 0.0418

Gnomad4 OTH AF: 0.0156

Alfa AF: 0.0353 Hom.: 187

Bravo AF: 0.0218

ESP6500AA AF: 0.00953 AC: 42

ESP6500EA AF: 0.0391 AC: 336

ExAC AF: 0.0259 AC: 3148

Asia WGS AF: 0.00404 AC: 14 AN: 3478

EpiCase AF: 0.0349

EpiControl AF: 0.0345

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	0.11
DANN	Benign	0.21
DEOGEN2	Benign	0.16	.;T;.;T;.;.
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.00068	N
LIST_S2	Benign	0.64	T;T;T;T;T;T
MetaRNN	Benign	0.0038	T;T;T;T;T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.32	.;N;.;.;N;N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	2.6	.;N;.;.;.;N
REVEL	Benign	0.17
Sift	Benign	1.0	.;T;.;.;.;T
Sift4G	Benign	1.0	T;T;T;T;T;T
Polyphen		0.0	.;.;B;.;.;.
Vest4		0.081, 0.12, 0.050
MPC		0.075
ClinPred		0.00048	T
GERP RS		-1.6
Varity_R		0.13
gMVP		0.19

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs61752561; hg19: chr19-51361382; COSMIC: COSV58101061; COSMIC: COSV58101061;