rs1654551

Positions:

chr19-50909412-A-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The ENST00000324041.6(KLK4):c.64T>G(p.Ser22Ala) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0847 in 1,613,798 control chromosomes in the GnomAD database, including 6,967 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S22W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.12 ( 1464 hom., cov: 31)

Exomes 𝑓: 0.081 ( 5503 hom. )

Consequence

KLK4
ENST00000324041.6 missense, splice_region

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -1.50

Variant links:

Genes affected

KLK4 (HGNC:6365): (kallikrein related peptidase 4) 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. This gene is one of the fifteen kallikrein subfamily members located in a cluster on chromosome 19. In some tissues its expression is hormonally regulated. The expression pattern of a similar mouse protein in murine developing teeth supports a role for the protein in the degradation of enamel proteins. Several transcript variants encoding different proteins have been found for this gene. [provided by RefSeq, Dec 2014]

KLK4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0026489794).

BP6

Variant 19-50909412-A-C is Benign according to our data. Variant chr19-50909412-A-C is described in ClinVar as [Benign]. Clinvar id is 1258657.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-50909412-A-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.229 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
KLK4	NM_004917.5 linkuse as main transcript	c.64T>G	p.Ser22Ala	missense_variant, splice_region_variant	3/6	ENST00000324041.6	NP_004908.4
KLK4	XM_011527545.4 linkuse as main transcript	c.64T>G	p.Ser22Ala	missense_variant, splice_region_variant	2/4		XP_011525847.1
KLK4	NM_001302961.2 linkuse as main transcript	c.-234T>G		splice_region_variant, 5_prime_UTR_variant	2/5		NP_001289890.1
KLK4	NR_126566.2 linkuse as main transcript	n.62-17T>G		splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
KLK4	ENST00000324041.6 linkuse as main transcript	c.64T>G	p.Ser22Ala	missense_variant, splice_region_variant	3/6	1	NM_004917.5	ENSP00000326159	P1
KLK4	ENST00000602148.1 linkuse as main transcript	c.64T>G	p.Ser22Ala	missense_variant, splice_region_variant, NMD_transcript_variant	2/5	1		ENSP00000472091
KLK4	ENST00000598305.5 linkuse as main transcript	c.-217-17T>G		splice_polypyrimidine_tract_variant, intron_variant, NMD_transcript_variant		1		ENSP00000469963
KLK4	ENST00000596876.1 linkuse as main transcript			upstream_gene_variant		1

Frequencies

GnomAD3 genomes

AF:

0.118

AC:

18000

AN:

152060

Hom.:

1456

Cov.:

show subpopulations

Gnomad AFR

AF:

0.232

Gnomad AMI

AF:

0.0220

Gnomad AMR

AF:

0.0652

Gnomad ASJ

AF:

0.0622

Gnomad EAS

AF:

0.103

Gnomad SAS

AF:

0.104

Gnomad FIN

AF:

0.0792

Gnomad MID

AF:

0.0696

Gnomad NFE

AF:

0.0744

Gnomad OTH

AF:

0.0943

GnomAD3 exomes

AF:

0.0881

AC:

22104

AN:

250912

Hom.:

1189

AF XY:

0.0889

AC XY:

12067

AN XY:

135728

show subpopulations

Gnomad AFR exome

AF:

0.233

Gnomad AMR exome

AF:

0.0445

Gnomad ASJ exome

AF:

0.0568

Gnomad EAS exome

AF:

0.109

Gnomad SAS exome

AF:

0.115

Gnomad FIN exome

AF:

0.0833

Gnomad NFE exome

AF:

0.0743

Gnomad OTH exome

AF:

0.0812

GnomAD4 exome

AF:

0.0812

AC:

118722

AN:

1461620

Hom.:

5503

Cov.:

AF XY:

0.0819

AC XY:

59582

AN XY:

727086

show subpopulations

Gnomad4 AFR exome

AF:

0.246

Gnomad4 AMR exome

AF:

0.0470

Gnomad4 ASJ exome

AF:

0.0582

Gnomad4 EAS exome

AF:

0.0996

Gnomad4 SAS exome

AF:

0.113

Gnomad4 FIN exome

AF:

0.0833

Gnomad4 NFE exome

AF:

0.0743

Gnomad4 OTH exome

AF:

0.0921

GnomAD4 genome

AF:

0.119

AC:

18046

AN:

152178

Hom.:

1464

Cov.:

AF XY:

0.118

AC XY:

8779

AN XY:

74402

show subpopulations

Gnomad4 AFR

AF:

0.233

Gnomad4 AMR

AF:

0.0651

Gnomad4 ASJ

AF:

0.0622

Gnomad4 EAS

AF:

0.104

Gnomad4 SAS

AF:

0.104

Gnomad4 FIN

AF:

0.0792

Gnomad4 NFE

AF:

0.0743

Gnomad4 OTH

AF:

0.0943

Alfa

AF:

0.0931

Hom.:

484

Bravo

AF:

0.124

TwinsUK

AF:

0.0804

AC:

298

ALSPAC

AF:

0.0698

AC:

269

ESP6500AA

AF:

0.212

AC:

933

ESP6500EA

AF:

0.0716

AC:

616

ExAC

AF:

0.0922

AC:

11194

Asia WGS

AF:

0.0990

AC:

344

AN:

3478

EpiCase

AF:

0.0709

EpiControl

AF:

0.0735

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 09, 2021	This variant is associated with the following publications: (PMID: 22970239) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.47

CADD

Benign

3.9

DANN

Benign

0.50

Eigen

Benign

-1.8

Eigen_PC

Benign

-1.9

FATHMM_MKL

Benign

0.011

LIST_S2

Benign

0.13

MetaRNN

Benign

0.0026

MetaSVM

Benign

-0.92

MutationTaster

Benign

1.0

PrimateAI

Benign

0.27

PROVEAN

Benign

-0.030

REVEL

Benign

0.18

Sift

Benign

0.76

Sift4G

Benign

0.91

Vest4

0.028

MPC

0.28

ClinPred

0.0088

GERP RS

-7.0

gMVP

0.48

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over