rs17632542

Positions:

• chr19-50858501-T-C

Variant summary

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

The NM_001648.2(KLK3):​c.536T>C​(p.Ile179Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0651 in 1,614,154 control chromosomes in the GnomAD database, including 3,857 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.049 (236 hom., cov: 32)
  • Exomes 𝑓: 0.067 (3621 hom.)
• Consequence: KLK3 NM_001648.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0520

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 (MetaRNN=0.0028503537).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0715 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KLK3	NM_001648.2	c.536T>C	p.Ile179Thr	missense_variant	4/5	ENST00000326003.7
KLK3	NM_001030047.1	c.536T>C	p.Ile179Thr	missense_variant	4/5
KLK3	NM_001030048.1	c.407T>C	p.Ile136Thr	missense_variant	4/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KLK3	ENST00000326003.7	c.536T>C	p.Ile179Thr	missense_variant	4/5	1	NM_001648.2	P1

Frequencies

GnomAD3 genomes AF: 0.0486 AC: 7401 AN: 152172 Hom.: 237 Cov.: 32

Gnomad AFR AF: 0.0124

Gnomad AMI AF: 0.185

Gnomad AMR AF: 0.0333

Gnomad ASJ AF: 0.0778

Gnomad EAS AF: 0.000963

Gnomad SAS AF: 0.0542

Gnomad FIN AF: 0.0546

Gnomad MID AF: 0.0601

Gnomad NFE AF: 0.0731

Gnomad OTH AF: 0.0483

GnomAD3 exomes AF: 0.0549 AC: 13814 AN: 251426 Hom.: 476 AF XY: 0.0571 AC XY: 7764 AN XY: 135882

Gnomad AFR exome AF: 0.00997

Gnomad AMR exome AF: 0.0277

Gnomad ASJ exome AF: 0.0798

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.0520

Gnomad FIN exome AF: 0.0598

Gnomad NFE exome AF: 0.0756

Gnomad OTH exome AF: 0.0656

GnomAD4 exome AF: 0.0668 AC: 97634 AN: 1461866 Hom.: 3621 Cov.: 36 AF XY: 0.0670 AC XY: 48759 AN XY: 727238

Gnomad4 AFR exome AF: 0.00932

Gnomad4 AMR exome AF: 0.0298

Gnomad4 ASJ exome AF: 0.0767

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.0537

Gnomad4 FIN exome AF: 0.0644

Gnomad4 NFE exome AF: 0.0737

Gnomad4 OTH exome AF: 0.0589

GnomAD4 genome AF: 0.0486 AC: 7402 AN: 152288 Hom.: 236 Cov.: 32 AF XY: 0.0471 AC XY: 3508 AN XY: 74458

Gnomad4 AFR AF: 0.0124

Gnomad4 AMR AF: 0.0332

Gnomad4 ASJ AF: 0.0778

Gnomad4 EAS AF: 0.000965

Gnomad4 SAS AF: 0.0543

Gnomad4 FIN AF: 0.0546

Gnomad4 NFE AF: 0.0732

Gnomad4 OTH AF: 0.0478

Alfa AF: 0.0684 Hom.: 863

Bravo AF: 0.0469

TwinsUK AF: 0.0758 AC: 281

ALSPAC AF: 0.0745 AC: 287

ESP6500AA AF: 0.0136 AC: 60

ESP6500EA AF: 0.0753 AC: 648

ExAC AF: 0.0552 AC: 6703

Asia WGS AF: 0.0150 AC: 53 AN: 3478

EpiCase AF: 0.0746

EpiControl AF: 0.0759

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.67
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	16
DANN	Benign	0.92
Eigen	Benign	-0.74
Eigen_PC	Benign	-0.88
FATHMM_MKL	Benign	0.052	N
LIST_S2	Benign	0.70	T;T;T;T;T;T;T;T
MetaRNN	Benign	0.0029	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.74	T
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.36	T
Sift4G	Uncertain	0.022	D;D;D;D;D;D;D;D
Polyphen		0.58	.;.;P;.;.;.;.;.
Vest4		0.059, 0.064, 0.063, 0.065
MPC		0.10
ClinPred		0.021	T
GERP RS		1.9
Varity_R		0.37
gMVP		0.49

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: rs17632542; hg19: chr19-51361757; COSMIC: COSV58099673; COSMIC: COSV58099673;