19-50856327-G-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_001648.2(KLK3):c.134G>A(p.Arg45His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000409 in 1,613,626 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000038 (0 hom.)
• Consequence: KLK3 NM_001648.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.80

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 Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06577283).
• BP6: Variant 19-50856327-G-A is Benign according to our data. Variant chr19-50856327-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 2390038.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KLK3	NM_001648.2	c.134G>A	p.Arg45His	missense_variant	2/5	ENST00000326003.7
KLK3	NM_001030047.1	c.134G>A	p.Arg45His	missense_variant	2/5
KLK3	NM_001030048.1	c.134G>A	p.Arg45His	missense_variant	2/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KLK3	ENST00000326003.7	c.134G>A	p.Arg45His	missense_variant	2/5	1	NM_001648.2	P1

Frequencies

GnomAD3 genomes AF: 0.0000657 AC: 10 AN: 152140 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000836 AC: 21 AN: 251338 Hom.: 0 AF XY: 0.0000736 AC XY: 10 AN XY: 135840

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000383 AC: 56 AN: 1461368 Hom.: 0 Cov.: 32 AF XY: 0.0000440 AC XY: 32 AN XY: 726974

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.000134

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000290

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000108

Gnomad4 OTH exome AF: 0.000149

GnomAD4 genome AF: 0.0000657 AC: 10 AN: 152258 Hom.: 0 Cov.: 31 AF XY: 0.0000269 AC XY: 2 AN XY: 74438

Gnomad4 AFR AF: 0.000144

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000773 Hom.: 0

Bravo AF: 0.0000642

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000906 AC: 11

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 07, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.41
Cadd	Benign	0.15
Dann	Benign	0.44
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.0012	N
LIST_S2	Benign	0.20	T;T;T;T;T;T;T
M_CAP	Benign	0.041	D
MetaRNN	Benign	0.066	T;T;T;T;T;T;T
MetaSVM	Benign	-0.71	T
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.27	T
Sift4G	Benign	0.54	T;T;T;T;T;T;T
Polyphen		0.0	.;.;B;.;.;.;.
Vest4		0.11, 0.11, 0.11, 0.086, 0.10, 0.11
MVP		0.77
MPC		0.095
ClinPred		0.0027	T
GERP RS		-1.7
Varity_R		0.18
gMVP		0.16

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

LitVar

Other links and lift over

dbSNP: rs139560851; hg19: chr19-51359583; COSMIC: COSV58100231; COSMIC: COSV58100231;