rs17632542

Variant names:

• chr19-50858501-T-C
• rs17632542
• NM_001648.2:c.536T>C

Variant summary

Our verdict is Benign. The variant received -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. 14/21 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 0.049 (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
• Publications: 90 publications found

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

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
KLK3	NM_001648.2	c.536T>C	p.Ile179Thr	missense_variant	Exon 4 of 5	ENST00000326003.7	NP_001639.1
KLK3	NM_001030047.1	c.536T>C	p.Ile179Thr	missense_variant	Exon 4 of 5		NP_001025218.1
KLK3	NM_001030048.1	c.407T>C	p.Ile136Thr	missense_variant	Exon 4 of 5		NP_001025219.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KLK3	ENST00000326003.7	c.536T>C	p.Ile179Thr	missense_variant	Exon 4 of 5	1	NM_001648.2	ENSP00000314151.1

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

GnomAD2 exomes AF: 0.0549 AC: 13814 AN: 251426 AF XY: 0.0571

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 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

African (AFR) AF: 0.00932 AC: 312 AN: 33478

American (AMR) AF: 0.0298 AC: 1331 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0767 AC: 2004 AN: 26136

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39700

South Asian (SAS) AF: 0.0537 AC: 4628 AN: 86258

European-Finnish (FIN) AF: 0.0644 AC: 3439 AN: 53418

Middle Eastern (MID) AF: 0.0621 AC: 358 AN: 5766

European-Non Finnish (NFE) AF: 0.0737 AC: 81999 AN: 1111994

Other (OTH) AF: 0.0589 AC: 3560 AN: 60392

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

African (AFR) AF: 0.0124 AC: 514 AN: 41578

American (AMR) AF: 0.0332 AC: 509 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.0778 AC: 270 AN: 3472

East Asian (EAS) AF: 0.000965 AC: 5 AN: 5182

South Asian (SAS) AF: 0.0543 AC: 262 AN: 4826

European-Finnish (FIN) AF: 0.0546 AC: 579 AN: 10610

Middle Eastern (MID) AF: 0.0616 AC: 18 AN: 292

European-Non Finnish (NFE) AF: 0.0732 AC: 4976 AN: 67998

Other (OTH) AF: 0.0478 AC: 101 AN: 2112

Alfa AF: 0.0663 Hom.: 1735

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
DEOGEN2	Uncertain	0.48	.;T;.;D;D;.;.;.
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
MutationAssessor	Benign	1.3	.;L;.;.;.;L;.;L
PhyloP100		-0.052
PrimateAI	Benign	0.36	T
PROVEAN	Uncertain	-2.6	.;D;.;.;.;.;.;D
REVEL	Benign	0.10
Sift	Uncertain	0.0050	.;D;.;.;.;.;.;D
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
Mutation Taster		=97/3	polymorphism (auto)

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

Other links and lift over

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