chr19-50856247-A-G

Variant names:

• chr19-50856247-A-G
• rs1135766
• NM_001648.2:c.54A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BA1

The NM_001648.2(KLK3):​c.54A>G​(p.Ala18Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.406 in 1,608,168 control chromosomes in the GnomAD database, including 137,079 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.37 (11211 hom., cov: 31)
  • Exomes 𝑓: 0.41 (125868 hom.)
• Consequence: KLK3 NM_001648.2 synonymous
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: -2.44
• Publications: 16 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.06).
• BP6: Variant 19-50856247-A-G is Benign according to our data. Variant chr19-50856247-A-G is described in ClinVar as Benign. ClinVar VariationId is 3060459.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP7: Synonymous conserved (PhyloP=-2.44 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.489 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KLK3	NM_001648.2	c.54A>G	p.Ala18Ala	synonymous_variant	Exon 2 of 5	ENST00000326003.7	NP_001639.1
KLK3	NM_001030047.1	c.54A>G	p.Ala18Ala	synonymous_variant	Exon 2 of 5		NP_001025218.1
KLK3	NM_001030048.1	c.54A>G	p.Ala18Ala	synonymous_variant	Exon 2 of 5		NP_001025219.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KLK3	ENST00000326003.7	c.54A>G	p.Ala18Ala	synonymous_variant	Exon 2 of 5	1	NM_001648.2	ENSP00000314151.1

Frequencies

GnomAD3 genomes AF: 0.371 AC: 56149 AN: 151488 Hom.: 11206 Cov.: 31

Gnomad AFR AF: 0.229

Gnomad AMI AF: 0.444

Gnomad AMR AF: 0.457

Gnomad ASJ AF: 0.380

Gnomad EAS AF: 0.506

Gnomad SAS AF: 0.227

Gnomad FIN AF: 0.462

Gnomad MID AF: 0.326

Gnomad NFE AF: 0.421

Gnomad OTH AF: 0.374

GnomAD2 exomes AF: 0.403 AC: 100794 AN: 250044 AF XY: 0.392

Gnomad AFR exome AF: 0.229

Gnomad AMR exome AF: 0.524

Gnomad ASJ exome AF: 0.385

Gnomad EAS exome AF: 0.515

Gnomad FIN exome AF: 0.457

Gnomad NFE exome AF: 0.411

Gnomad OTH exome AF: 0.400

GnomAD4 exome AF: 0.410 AC: 596503 AN: 1456562 Hom.: 125868 Cov.: 36 AF XY: 0.404 AC XY: 293048 AN XY: 724746

African (AFR) AF: 0.218 AC: 7271 AN: 33336

American (AMR) AF: 0.511 AC: 22822 AN: 44638

Ashkenazi Jewish (ASJ) AF: 0.387 AC: 10080 AN: 26032

East Asian (EAS) AF: 0.513 AC: 20327 AN: 39658

South Asian (SAS) AF: 0.238 AC: 20445 AN: 86058

European-Finnish (FIN) AF: 0.462 AC: 24619 AN: 53328

Middle Eastern (MID) AF: 0.298 AC: 1374 AN: 4610

European-Non Finnish (NFE) AF: 0.420 AC: 465582 AN: 1108772

Other (OTH) AF: 0.399 AC: 23983 AN: 60130

GnomAD4 genome AF: 0.371 AC: 56174 AN: 151606 Hom.: 11211 Cov.: 31 AF XY: 0.371 AC XY: 27443 AN XY: 74064

African (AFR) AF: 0.229 AC: 9477 AN: 41358

American (AMR) AF: 0.457 AC: 6967 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.380 AC: 1317 AN: 3462

East Asian (EAS) AF: 0.506 AC: 2600 AN: 5142

South Asian (SAS) AF: 0.227 AC: 1083 AN: 4772

European-Finnish (FIN) AF: 0.462 AC: 4852 AN: 10504

Middle Eastern (MID) AF: 0.310 AC: 91 AN: 294

European-Non Finnish (NFE) AF: 0.422 AC: 28584 AN: 67810

Other (OTH) AF: 0.380 AC: 802 AN: 2110

Alfa AF: 0.386 Hom.: 5100

Bravo AF: 0.368

Asia WGS AF: 0.363 AC: 1263 AN: 3478

EpiCase AF: 0.407

EpiControl AF: 0.407

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

KLK3-related disorder Benign:1

Oct 18, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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_noAF	Benign	-1.1
CADD	Benign	0.016
DANN	Benign	0.20
PhyloP100		-2.4
Mutation Taster		=100/0	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: rs1135766; hg19: chr19-51359503; COSMIC: COSV58100707; COSMIC: COSV58100707;