rs886037956
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1PS1_ModeratePM2PP5_Very_Strong
The NM_017644.3(KLHL24):c.1A>G(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
7
5
3
Clinical Significance
Conservation
PhyloP100: 8.70
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 20 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 931095
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 3-183650357-A-G is Pathogenic according to our data. Variant chr3-183650357-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 264648.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-183650357-A-G is described in Lovd as [Pathogenic]. Variant chr3-183650357-A-G is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KLHL24 | NM_017644.3 | c.1A>G | p.Met1? | start_lost | 3/8 | ENST00000242810.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KLHL24 | ENST00000242810.11 | c.1A>G | 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:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Epidermolysis bullosa simplex 6, generalized, with scarring and hair loss Pathogenic:3
Pathogenic, no assertion criteria provided | literature only | OMIM | Feb 08, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein | Jan 15, 2022 | ACMG classification criteria: PS3 supporting, PS4 strong, PM2 moderate, PM6 very strong, PP1 supporting - |
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory of Medical Genetics, National & Kapodistrian University of Athens | Jul 27, 2018 | PS3, PM2, PM6, PP3, PP4, PP5 - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Feb 25, 2022 | Follow-up reports have identified evidence of cardiac involvement such as increased blood levels of a biomarker for heart disease, significant cardiac dysfunction by imaging, or adult-onset dilated cardiomyopathy (DCM) in a high proportion of these patients, and neurological involvement in a smaller proportion (Schwieger-Briel et al., 2018; Yenamandra et al., 2018); The c.1 A>G variant alters the initiator Methionine codon, and the resultant protein is described as p.Met1? using a question mark to signify that it is not certain if the loss of Met1 means that all protein translation is completely prevented or if an abnormal protein is produced using an alternate Met; however, published functional studies demonstrate that a downstream in-frame Met initiation codon was used to initiate translation of a protein missing the initial 28 amino acids of the KLHL24 protein (denoted p.Val2_Met29del or KLHL24delta28) in some patients (Lin et al., 2016; He et al., 2016); Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27798626, 27889062, 28111128, 30120936, 29779254, 34292882, 34008892, 32484238) - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 02, 2023 | This sequence change affects the initiator methionine of the KLHL24 mRNA. The next in-frame methionine is located at codon 29. Loss-of-function variants in KLHL24 are expected to cause autosomal recessive hypertrophic cardiomyopathy (PMID: 30715372). However, initiator codon variants and truncations that occur before p.Met29 are unlikely to result in loss of function (PMID: 35975634). This variant is not present in population databases (gnomAD no frequency). Disruption of the initiator codon has been observed in individual(s) with autosomal dominant epidermolysis bullosa (PMID: 27889062). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 264648). For these reasons, this variant has been classified as Pathogenic. - |
Epidermolysis bullosa simplex, Koebner type Pathogenic:1
Pathogenic, criteria provided, single submitter | in vitro;research | Clinical Genetics Laboratory of Dermatology, Peking University First Hospital | Sep 01, 2016 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Benign
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
PROVEAN
Benign
N;N;D;N;D;N;N;N;N;N;N
REVEL
Uncertain
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
B;.;.;.;.;.;.;.;B;.;B
Vest4
MutPred
Gain of catalytic residue at M1 (P = 0.0298);Gain of catalytic residue at M1 (P = 0.0298);Gain of catalytic residue at M1 (P = 0.0298);Gain of catalytic residue at M1 (P = 0.0298);Gain of catalytic residue at M1 (P = 0.0298);Gain of catalytic residue at M1 (P = 0.0298);Gain of catalytic residue at M1 (P = 0.0298);Gain of catalytic residue at M1 (P = 0.0298);Gain of catalytic residue at M1 (P = 0.0298);Gain of catalytic residue at M1 (P = 0.0298);Gain of catalytic residue at M1 (P = 0.0298);
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