chr19-50908596-C-T
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Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_004917.5(KLK4):c.458G>A(p.Trp153Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000111 in 1,614,264 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.00062 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000058 ( 1 hom. )
Consequence
KLK4
NM_004917.5 stop_gained
NM_004917.5 stop_gained
Scores
2
4
1
Clinical Significance
Conservation
PhyloP100: 2.50
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 19-50908596-C-T is Pathogenic according to our data. Variant chr19-50908596-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 6079.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KLK4 | NM_004917.5 | c.458G>A | p.Trp153Ter | stop_gained | 4/6 | ENST00000324041.6 | |
KLK4 | NM_001302961.2 | c.173G>A | p.Trp58Ter | stop_gained | 3/5 | ||
KLK4 | XM_011527545.4 | c.458G>A | p.Trp153Ter | stop_gained | 3/4 | ||
KLK4 | NR_126566.2 | n.451G>A | non_coding_transcript_exon_variant | 3/5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KLK4 | ENST00000324041.6 | c.458G>A | p.Trp153Ter | stop_gained | 4/6 | 1 | NM_004917.5 | P1 |
Frequencies
GnomAD3 genomes AF: 0.000617 AC: 94AN: 152252Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000131 AC: 33AN: 251394Hom.: 1 AF XY: 0.0000883 AC XY: 12AN XY: 135880
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GnomAD4 exome AF: 0.0000581 AC: 85AN: 1461894Hom.: 1 Cov.: 32 AF XY: 0.0000468 AC XY: 34AN XY: 727248
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GnomAD4 genome AF: 0.000617 AC: 94AN: 152370Hom.: 0 Cov.: 32 AF XY: 0.000617 AC XY: 46AN XY: 74512
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ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Amelogenesis imperfecta type 2A1 Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Mar 25, 2024 | The p.Trp153X variant in KLK4 has been reported in 2 homozygous individuals with amelogenesis imperfecta and segregated with disease in at least 1 affected relative from 1 family (Hart 2004 PMID: 15235027, Wright 2011 PMID: 21597265). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 6079) and has been identified in 0.22% (92/41468) of African/African American chromosomes by gnomAD (http://gnomad.broadinstitute.org, v4.0.0). This nonsense variant leads to a premature termination codon at position 153, which is predicted to lead to a truncated or absent protein. Loss of function variants in the KLK4 gene have been reported in individuals with autosomal recessive amelogenesis imperfecta (Wang 2013 PMID: 23355523, Seymen 2015 PMID: 26124219, Smith 2017 PMID: 28611678, Lee 2022 PMID: 35207639). Additionally, studies have shown that KLK4 null mice had defective enamel, recapitulating features of the human phenotype (Simmer 2009 PubMed: 19578120, Nunez 2016 PMID: 26620968). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive amelogenesis imperfecta. ACMG/AMP Criteria applied: PVS1, PM3. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 01, 2011 | - - |
Computational scores
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Name
Calibrated prediction
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BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
A;A
Vest4
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Splicing
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at