Genetic Variant NM_001648.2:c.48T>A (chr19-50856241-T-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001648.2(KLK3):c.48T>A(p.Gly16Gly) variant causes a splice region, synonymous 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. 2/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. G16G) has been classified as Benign.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

KLK3
NM_001648.2 splice_region, synonymous

Scores

Splicing: ADA: 0.0005357

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.529

Publications

20 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: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_addAF=-0.470916).

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
KLK3	NM_001648.2	MANE Select	c.48T>A	p.Gly16Gly	splice_region synonymous	Exon 2 of 5	NP_001639.1
KLK3	NM_001030047.1		c.48T>A	p.Gly16Gly	splice_region synonymous	Exon 2 of 5	NP_001025218.1
KLK3	NM_001030048.1		c.48T>A	p.Gly16Gly	splice_region synonymous	Exon 2 of 5	NP_001025219.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
KLK3	ENST00000326003.7	TSL:1 MANE Select	c.48T>A	p.Gly16Gly	splice_region synonymous	Exon 2 of 5	ENSP00000314151.1
KLK3	ENST00000360617.7	TSL:1	c.48T>A	p.Gly16Gly	splice_region synonymous	Exon 2 of 5	ENSP00000353829.2
KLK3	ENST00000593997.5	TSL:1	c.48T>A	p.Gly16Gly	splice_region synonymous	Exon 2 of 4	ENSP00000472907.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

1458922

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

725796

African (AFR)

AF:

0.00

AC:

AN:

33404

American (AMR)

AF:

0.00

AC:

AN:

44650

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26008

East Asian (EAS)

AF:

0.00

AC:

AN:

39680

South Asian (SAS)

AF:

0.00

AC:

AN:

86052

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53318

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4556

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111036

Other (OTH)

AF:

0.00

AC:

AN:

60218

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.91

CADD

Benign

1.3

(source)

DANN

Benign

0.23

FATHMM_MKL

Benign

0.20

PhyloP100

-0.53

GERP RS

-1.4

Mutation Taster

=95/5

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00054

dbscSNV1_RF

Benign

0.052

SpliceAI score (max)

0.21

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.21

Position offset: -1

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