19-50856321-C-T

Variant names:

• chr19-50856321-C-T
• NM_001648.2:c.128C>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001648.2(KLK3):​c.128C>T​(p.Ala43Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,304 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: KLK3 NM_001648.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0250

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17247725).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KLK3	NM_001648.2	c.128C>T	p.Ala43Val	missense_variant	Exon 2 of 5	ENST00000326003.7	NP_001639.1
KLK3	NM_001030047.1	c.128C>T	p.Ala43Val	missense_variant	Exon 2 of 5		NP_001025218.1
KLK3	NM_001030048.1	c.128C>T	p.Ala43Val	missense_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.128C>T	p.Ala43Val	missense_variant	Exon 2 of 5	1	NM_001648.2	ENSP00000314151.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461304 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 726954

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.071	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	11
DANN	Benign	0.96
DEOGEN2	Benign	0.15	.;T;.;T;.;.;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.013	N
LIST_S2	Benign	0.35	T;T;T;T;T;T;T
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.17	T;T;T;T;T;T;T
MetaSVM	Benign	-0.68	T
MutationAssessor	Benign	-0.045	.;N;.;.;N;N;N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	0.37	.;N;.;.;.;.;N
REVEL	Benign	0.20
Sift	Benign	0.044	.;D;.;.;.;.;T
Sift4G	Benign	0.18	T;T;T;T;T;T;T
Polyphen		0.075	.;.;B;.;.;.;.
Vest4		0.17, 0.17, 0.18, 0.18, 0.17, 0.17
MutPred		0.54		.;Loss of catalytic residue at A43 (P = 0.1989);Loss of catalytic residue at A43 (P = 0.1989);Loss of catalytic residue at A43 (P = 0.1989);Loss of catalytic residue at A43 (P = 0.1989);Loss of catalytic residue at A43 (P = 0.1989);Loss of catalytic residue at A43 (P = 0.1989);
MVP		0.80
MPC		0.10
ClinPred		0.35	T
GERP RS		-1.7
Varity_R		0.10
gMVP		0.19

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-51359577; COSMIC: COSV58099605; COSMIC: COSV58099605;