19-50856309-A-G

Variant names:

• chr19-50856309-A-G
• rs200712655
• NM_001648.2:c.116A>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001648.2(KLK3):​c.116A>G​(p.Gln39Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,254 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q39L) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: KLK3 NM_001648.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.990
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001648.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KLK3	NM_001648.2	MANE Select	c.116A>G	p.Gln39Arg	missense	Exon 2 of 5	NP_001639.1	Q546G3
	KLK3	NM_001030047.1		c.116A>G	p.Gln39Arg	missense	Exon 2 of 5	NP_001025218.1	P07288-2
	KLK3	NM_001030048.1		c.116A>G	p.Gln39Arg	missense	Exon 2 of 5	NP_001025219.1	P07288-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KLK3	ENST00000326003.7	TSL:1 MANE Select	c.116A>G	p.Gln39Arg	missense	Exon 2 of 5	ENSP00000314151.1	P07288-1
	KLK3	ENST00000360617.7	TSL:1	c.116A>G	p.Gln39Arg	missense	Exon 2 of 5	ENSP00000353829.2	P07288-2
	KLK3	ENST00000593997.5	TSL:1	c.116A>G	p.Gln39Arg	missense	Exon 2 of 4	ENSP00000472907.1	P07288-5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461254 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 726932

African (AFR) AF: 0.00 AC: 0 AN: 33462

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86226

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53404

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5288

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111988

Other (OTH) AF: 0.0000331 AC: 2 AN: 60340

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Uncertain	0.075	D
BayesDel_noAF	Uncertain	-0.070
CADD	Uncertain	24
DANN	Uncertain	0.99
Eigen	Benign	0.18
Eigen_PC	Benign	-0.065
FATHMM_MKL	Uncertain	0.86	D
M_CAP	Benign	0.027	D
PhyloP100		0.99
ClinPred		0.89	D
GERP RS		1.0
La Branchor		0.41
Varity_R		0.56
Mutation Taster		=72/28	polymorphism

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: rs200712655; hg19: chr19-51359565;