rs1057515580
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1PS1_ModeratePM2PP5_Moderate
The NM_017644.3(KLHL24):c.2T>C(p.Met1?) variant causes a start lost change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).
Frequency
Genomes: not found (cov: 32)
Consequence
KLHL24
NM_017644.3 start_lost
NM_017644.3 start_lost
Scores
8
4
3
Clinical Significance
Conservation
PhyloP100: 7.46
Genes affected
KLHL24 (HGNC:25947): (kelch like family member 24) The protein encoded by this gene is a ubiquitin ligase substrate receptor and is regulated by autoubiquitination. Variations in the translation initiation codon of this gene have been found, which result in an N-terminally truncated but more stable protein due to loss of the autoubiquitination function. The more stable mutant protein causes an increased ubiquitin and degradation of keratin 14, which leads to skin fragility and the potentially life-threatening disease epidermolysis bullosa. The encoded protein is also involved in the regulation of kainate receptors. [provided by RefSeq, Mar 2017]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 14 ACMG points.
PVS1
?
Start lost variant, no new inframe start found.
PS1
?
Another start lost variant in NM_017644.3 (KLHL24) was described as [Pathogenic] in ClinVar as 264648
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 3-183650358-T-C is Pathogenic according to our data. Variant chr3-183650358-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 370042.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KLHL24 | NM_017644.3 | c.2T>C | p.Met1? | start_lost | 3/8 | ENST00000242810.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KLHL24 | ENST00000242810.11 | c.2T>C | p.Met1? | start_lost | 3/8 | 1 | NM_017644.3 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Cov.: 29
GnomAD4 exome
Cov.:
29
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Epidermolysis bullosa simplex 6, generalized, with scarring and hair loss Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Feb 08, 2023 | - - |
Epidermolysis bullosa simplex, Koebner type Pathogenic:1
Pathogenic, criteria provided, single submitter | research | Lab of Molecular Dermatology, University Medical Center Freiburg | Aug 01, 2016 | This variant causes skin fragility as demonstrated by the correlation between genotype and phenotype in the family and functional studies. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
T;T;.;T;T;T;.;.;T;T;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Uncertain
D
MutationTaster
Benign
D;D;D
PROVEAN
Benign
N;N;D;N;D;D;N;N;N;N;N
REVEL
Pathogenic
Sift
Pathogenic
D;D;D;D;D;D;D;D;D;D;D
Sift4G
Pathogenic
D;D;D;D;D;D;D;D;D;D;D
Polyphen
P;.;.;.;.;.;.;.;P;.;P
Vest4
MutPred
Gain of catalytic residue at M1 (P = 0.0059);Gain of catalytic residue at M1 (P = 0.0059);Gain of catalytic residue at M1 (P = 0.0059);Gain of catalytic residue at M1 (P = 0.0059);Gain of catalytic residue at M1 (P = 0.0059);Gain of catalytic residue at M1 (P = 0.0059);Gain of catalytic residue at M1 (P = 0.0059);Gain of catalytic residue at M1 (P = 0.0059);Gain of catalytic residue at M1 (P = 0.0059);Gain of catalytic residue at M1 (P = 0.0059);Gain of catalytic residue at M1 (P = 0.0059);
MVP
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at