19-50907002-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_004917.5(KLK4):c.697G>A(p.Val233Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0017 in 1,614,134 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0010 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0018 (2 hom.)
• Consequence: KLK4 NM_004917.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -5.09

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]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.06443933).
• BP6: Variant 19-50907002-C-T is Benign according to our data. Variant chr19-50907002-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 986162.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KLK4	NM_004917.5	c.697G>A	p.Val233Met	missense_variant	6/6	ENST00000324041.6
KLK4	NM_001302961.2	c.412G>A	p.Val138Met	missense_variant	5/5
KLK4	NR_126566.2	n.686G>A		non_coding_transcript_exon_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KLK4	ENST00000324041.6	c.697G>A	p.Val233Met	missense_variant	6/6	1	NM_004917.5	P1

Frequencies

GnomAD3 genomes AF: 0.00101 AC: 153 AN: 152132 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00115

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00191

Gnomad OTH AF: 0.000959

GnomAD3 exomes AF: 0.000855 AC: 215 AN: 251488 Hom.: 0 AF XY: 0.000824 AC XY: 112 AN XY: 135916

Gnomad AFR exome AF: 0.000615

Gnomad AMR exome AF: 0.000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000489

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.000185

Gnomad NFE exome AF: 0.00156

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.00178 AC: 2595 AN: 1461884 Hom.: 2 Cov.: 32 AF XY: 0.00171 AC XY: 1244 AN XY: 727242

Gnomad4 AFR exome AF: 0.000299

Gnomad4 AMR exome AF: 0.000335

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000428

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.000168

Gnomad4 NFE exome AF: 0.00217

Gnomad4 OTH exome AF: 0.00205

GnomAD4 genome AF: 0.00100 AC: 153 AN: 152250 Hom.: 1 Cov.: 32 AF XY: 0.000806 AC XY: 60 AN XY: 74430

Gnomad4 AFR AF: 0.000337

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00116

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00191

Gnomad4 OTH AF: 0.000949

Alfa AF: 0.00145 Hom.: 0

Bravo AF: 0.00107

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00221 AC: 19

ExAC AF: 0.000906 AC: 110

EpiCase AF: 0.00158

EpiControl AF: 0.00142

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 13, 2018

- -

KLK4-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 22, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.35
Cadd	Benign	0.025
Dann	Uncertain	0.99
Eigen	Benign	-0.89
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.0034	N
LIST_S2	Benign	0.22	T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.064	T
MetaSVM	Benign	-0.37	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	0.16	N
REVEL	Benign	0.26
Sift	Benign	0.18	T
Sift4G	Benign	0.22	T
Vest4		0.087
MVP		0.56
MPC		0.35
ClinPred		0.79	D
GERP RS		-2.3
gMVP		0.19

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

Other links and lift over

dbSNP: rs140350753; hg19: chr19-51410258; COSMIC: COSV60676427; COSMIC: COSV60676427;