19-50856287-G-A

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.94G>A(p.Glu32Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00212 in 1,613,256 control chromosomes in the GnomAD database, including 94 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0036 (16 hom., cov: 31)
  • Exomes 𝑓: 0.0020 (78 hom.)
• Consequence: KLK3 NM_001648.2 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -3.38

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 (MetaRNN=0.004591286).
• BP6: Variant 19-50856287-G-A is Benign according to our data. Variant chr19-50856287-G-A is described in ClinVar as [Benign]. Clinvar id is 784838.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0525 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KLK3	NM_001648.2	c.94G>A	p.Glu32Lys	missense_variant	2/5	ENST00000326003.7
KLK3	NM_001030047.1	c.94G>A	p.Glu32Lys	missense_variant	2/5
KLK3	NM_001030048.1	c.94G>A	p.Glu32Lys	missense_variant	2/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KLK3	ENST00000326003.7	c.94G>A	p.Glu32Lys	missense_variant	2/5	1	NM_001648.2	P1

Frequencies

GnomAD3 genomes AF: 0.00352 AC: 536 AN: 152190 Hom.: 15 Cov.: 31

Gnomad AFR AF: 0.000603

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0302

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00695

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.00816 AC: 2050 AN: 251328 Hom.: 58 AF XY: 0.00628 AC XY: 853 AN XY: 135836

Gnomad AFR exome AF: 0.000677

Gnomad AMR exome AF: 0.0550

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00533

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000528

Gnomad OTH exome AF: 0.00522

GnomAD4 exome AF: 0.00197 AC: 2877 AN: 1460948 Hom.: 78 Cov.: 32 AF XY: 0.00172 AC XY: 1248 AN XY: 726806

Gnomad4 AFR exome AF: 0.000389

Gnomad4 AMR exome AF: 0.0543

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00645

Gnomad4 SAS exome AF: 0.0000928

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000468

Gnomad4 OTH exome AF: 0.00197

GnomAD4 genome AF: 0.00357 AC: 543 AN: 152308 Hom.: 16 Cov.: 31 AF XY: 0.00385 AC XY: 287 AN XY: 74464

Gnomad4 AFR AF: 0.000601

Gnomad4 AMR AF: 0.0306

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00697

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.000482 Hom.: 1

Bravo AF: 0.00617

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00599 AC: 727

Asia WGS AF: 0.00404 AC: 14 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jun 22, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.32
Cadd	Benign	0.24
Dann	Uncertain	0.99
DEOGEN2	Benign	0.32	T;.;T;.;.;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.013	N
LIST_S2	Benign	0.049	T;T;T;T;T;T
MetaRNN	Benign	0.0046	T;T;T;T;T;T
MetaSVM	Benign	-0.57	T
MutationAssessor	Benign	-0.15	N;.;.;N;N;N
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.28	T
PROVEAN	Uncertain	-2.6	D;.;.;.;.;D
REVEL	Uncertain	0.40
Sift	Benign	0.23	T;.;.;.;.;T
Sift4G	Benign	0.65	T;T;T;T;T;T
Polyphen		0.92	.;P;.;.;.;.
Vest4		0.16
MVP		0.77
MPC		0.40
ClinPred		0.054	T
GERP RS		-4.2
Varity_R		0.21
gMVP		0.29

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: rs2271092; hg19: chr19-51359543;