chr19-50854757-G-A

Variant names:

• chr19-50854757-G-A
• rs266882
• NM_001648.2:c.-199G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001648.2(KLK3):​c.-199G>A variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.48 in 151,882 control chromosomes in the GnomAD database, including 18,191 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.48 (18191 hom., cov: 30)
• Consequence: KLK3 NM_001648.2 upstream_gene
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.419
• Publications: 39 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 (BayesDel_noAF=-0.96).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.536 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KLK3	NM_001648.2	c.-199G>A		upstream_gene_variant		ENST00000326003.7	NP_001639.1
KLK3	NM_001030047.1	c.-199G>A		upstream_gene_variant			NP_001025218.1
KLK3	NM_001030048.1	c.-199G>A		upstream_gene_variant			NP_001025219.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KLK3	ENST00000326003.7	c.-199G>A		upstream_gene_variant		1	NM_001648.2	ENSP00000314151.1

Frequencies

GnomAD3 genomes AF: 0.480 AC: 72895 AN: 151764 Hom.: 18181 Cov.: 30

Gnomad AFR AF: 0.542

Gnomad AMI AF: 0.419

Gnomad AMR AF: 0.366

Gnomad ASJ AF: 0.435

Gnomad EAS AF: 0.162

Gnomad SAS AF: 0.399

Gnomad FIN AF: 0.523

Gnomad MID AF: 0.465

Gnomad NFE AF: 0.495

Gnomad OTH AF: 0.464

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.480 AC: 72935 AN: 151882 Hom.: 18191 Cov.: 30 AF XY: 0.477 AC XY: 35399 AN XY: 74264

African (AFR) AF: 0.542 AC: 22451 AN: 41404

American (AMR) AF: 0.365 AC: 5574 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.435 AC: 1509 AN: 3466

East Asian (EAS) AF: 0.163 AC: 841 AN: 5164

South Asian (SAS) AF: 0.399 AC: 1919 AN: 4808

European-Finnish (FIN) AF: 0.523 AC: 5523 AN: 10564

Middle Eastern (MID) AF: 0.459 AC: 135 AN: 294

European-Non Finnish (NFE) AF: 0.495 AC: 33633 AN: 67890

Other (OTH) AF: 0.459 AC: 969 AN: 2112

Alfa AF: 0.485 Hom.: 11283

Bravo AF: 0.469

Asia WGS AF: 0.288 AC: 1005 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	13
DANN	Benign	0.21
PhyloP100		-0.42
PromoterAI		-0.020	Neutral
Mutation Taster		=100/0	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs266882; hg19: chr19-51358013;