Genetic Variant NM_001648.2:c.145G>A (chr19-50856338-G-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001648.2(KLK3):c.145G>A(p.Val49Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. 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. V49L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Consequence

KLK3
NM_001648.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.84

Publications

0 publications found

Variant links:

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]

KLK3 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.19065091).

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KLK3	NM_001648.2	MANE Select	c.145G>A	p.Val49Ile	missense	Exon 2 of 5	NP_001639.1	Q546G3
KLK3	NM_001030047.1		c.145G>A	p.Val49Ile	missense	Exon 2 of 5	NP_001025218.1	P07288-2
KLK3	NM_001030048.1		c.145G>A	p.Val49Ile	missense	Exon 2 of 5	NP_001025219.1	P07288-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KLK3	ENST00000326003.7	TSL:1 MANE Select	c.145G>A	p.Val49Ile	missense	Exon 2 of 5	ENSP00000314151.1	P07288-1
KLK3	ENST00000360617.7	TSL:1	c.145G>A	p.Val49Ile	missense	Exon 2 of 5	ENSP00000353829.2	P07288-2
KLK3	ENST00000593997.5	TSL:1	c.145G>A	p.Val49Ile	missense	Exon 2 of 4	ENSP00000472907.1	P07288-5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.44

CADD

Benign

0.0040

(source)

DANN

Benign

0.73

DEOGEN2

Benign

0.16

Eigen

Benign

-2.0

Eigen_PC

Benign

-2.1

FATHMM_MKL

Benign

0.0036

LIST_S2

Benign

0.018

M_CAP

Benign

0.026

MetaRNN

Benign

0.19

MetaSVM

Benign

-0.73

MutationAssessor

Benign

0.28

PhyloP100

-2.8

PrimateAI

Benign

0.34

PROVEAN

Benign

-0.31

REVEL

Benign

0.23

Sift

Benign

0.43

Sift4G

Benign

0.56

Polyphen

0.0

Vest4

0.081

MutPred

0.44

Loss of sheet (P = 0.1398)

MVP

0.25

MPC

0.064

ClinPred

0.12

GERP RS

-5.2

Varity_R

0.090

gMVP

0.15

Mutation Taster

=95/5

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over