19-50907062-A-G
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Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP3_StrongPP5
The NM_004917.5(KLK4):āc.637T>Cā(p.Cys213Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000867 in 1,614,068 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).
Frequency
Genomes: š 0.0000066 ( 0 hom., cov: 32)
Exomes š: 0.0000089 ( 0 hom. )
Consequence
KLK4
NM_004917.5 missense
NM_004917.5 missense
Scores
8
8
1
Clinical Significance
Conservation
PhyloP100: 5.16
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 Likely_pathogenic. Variant got 7 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.99
PP5
Variant 19-50907062-A-G is Pathogenic according to our data. Variant chr19-50907062-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 1327588.Status of the report is no_assertion_criteria_provided, 0 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
KLK4 | NM_004917.5 | c.637T>C | p.Cys213Arg | missense_variant | 6/6 | ENST00000324041.6 | NP_004908.4 | |
KLK4 | NM_001302961.2 | c.352T>C | p.Cys118Arg | missense_variant | 5/5 | NP_001289890.1 | ||
KLK4 | NR_126566.2 | n.626T>C | non_coding_transcript_exon_variant | 5/5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
KLK4 | ENST00000324041.6 | c.637T>C | p.Cys213Arg | missense_variant | 6/6 | 1 | NM_004917.5 | ENSP00000326159.1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152216Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251326Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135866
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GnomAD4 exome AF: 0.00000889 AC: 13AN: 1461852Hom.: 0 Cov.: 32 AF XY: 0.00000963 AC XY: 7AN XY: 727222
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GnomAD4 genome AF: 0.00000657 AC: 1AN: 152216Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74374
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link
Submissions by phenotype
Amelogenesis imperfecta Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Dental Genetics Laboratory, Seoul National University School of Dentistry | - | - - |
Computational scores
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Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D
MetaSVM
Pathogenic
D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D
REVEL
Pathogenic
Sift
Pathogenic
D
Sift4G
Uncertain
D
Vest4
MutPred
Gain of disorder (P = 0.036);
MVP
MPC
ClinPred
D
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gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at