19-50860142-C-T

Variant names:

• chr19-50860142-C-T
• rs1058205
• ENST00000422986.6:n.*457C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000422986.6(KLK3):​n.*457C>T variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.788 in 1,585,160 control chromosomes in the GnomAD database, including 496,373 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.74 (42412 hom., cov: 32)
  • Exomes 𝑓: 0.79 (453961 hom.)
• Consequence: KLK3 ENST00000422986.6 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.170
• Publications: 56 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 19-50860142-C-T is Benign according to our data. Variant chr19-50860142-C-T is described in ClinVar as Benign. ClinVar VariationId is 1288242.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.819 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KLK3	NM_001648.2	c.*15C>T		3_prime_UTR_variant	Exon 5 of 5	ENST00000326003.7	NP_001639.1
KLK3	NM_001030047.1	c.*526C>T		3_prime_UTR_variant	Exon 5 of 5		NP_001025218.1
KLK3	NM_001030048.1	c.*15C>T		3_prime_UTR_variant	Exon 5 of 5		NP_001025219.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KLK3	ENST00000326003.7	c.*15C>T		3_prime_UTR_variant	Exon 5 of 5	1	NM_001648.2	ENSP00000314151.1

Frequencies

GnomAD3 genomes AF: 0.739 AC: 112266 AN: 151962 Hom.: 42398 Cov.: 32

Gnomad AFR AF: 0.597

Gnomad AMI AF: 0.774

Gnomad AMR AF: 0.743

Gnomad ASJ AF: 0.748

Gnomad EAS AF: 0.584

Gnomad SAS AF: 0.629

Gnomad FIN AF: 0.861

Gnomad MID AF: 0.709

Gnomad NFE AF: 0.824

Gnomad OTH AF: 0.731

GnomAD2 exomes AF: 0.751 AC: 185689 AN: 247176 AF XY: 0.753

Gnomad AFR exome AF: 0.597

Gnomad AMR exome AF: 0.715

Gnomad ASJ exome AF: 0.755

Gnomad EAS exome AF: 0.590

Gnomad FIN exome AF: 0.861

Gnomad NFE exome AF: 0.816

Gnomad OTH exome AF: 0.765

GnomAD4 exome AF: 0.793 AC: 1136113 AN: 1433080 Hom.: 453961 Cov.: 24 AF XY: 0.790 AC XY: 563649 AN XY: 713806

African (AFR) AF: 0.593 AC: 19501 AN: 32892

American (AMR) AF: 0.715 AC: 31534 AN: 44130

Ashkenazi Jewish (ASJ) AF: 0.759 AC: 19457 AN: 25634

East Asian (EAS) AF: 0.600 AC: 23682 AN: 39466

South Asian (SAS) AF: 0.650 AC: 55343 AN: 85132

European-Finnish (FIN) AF: 0.858 AC: 45701 AN: 53250

Middle Eastern (MID) AF: 0.701 AC: 3983 AN: 5684

European-Non Finnish (NFE) AF: 0.819 AC: 891094 AN: 1087554

Other (OTH) AF: 0.772 AC: 45818 AN: 59338

GnomAD4 genome AF: 0.739 AC: 112326 AN: 152080 Hom.: 42412 Cov.: 32 AF XY: 0.736 AC XY: 54749 AN XY: 74342

African (AFR) AF: 0.597 AC: 24738 AN: 41454

American (AMR) AF: 0.742 AC: 11346 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.748 AC: 2594 AN: 3470

East Asian (EAS) AF: 0.584 AC: 3002 AN: 5142

South Asian (SAS) AF: 0.629 AC: 3036 AN: 4830

European-Finnish (FIN) AF: 0.861 AC: 9124 AN: 10602

Middle Eastern (MID) AF: 0.690 AC: 203 AN: 294

European-Non Finnish (NFE) AF: 0.824 AC: 56029 AN: 67976

Other (OTH) AF: 0.732 AC: 1548 AN: 2114

Alfa AF: 0.788 Hom.: 204511

Bravo AF: 0.723

Asia WGS AF: 0.602 AC: 2092 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Oct 29, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 25691096) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.44
DANN	Benign	0.49
PhyloP100		-0.17
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: rs1058205; hg19: chr19-51363398;