rs58330629
Variant summary
Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PS1_ModeratePM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000526.5(KRT14):c.374G>T(p.Arg125Leu) variant causes a missense change. 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 (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R125G) has been classified as Uncertain significance.
Frequency
Consequence
NM_000526.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 20 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KRT14 | NM_000526.5 | c.374G>T | p.Arg125Leu | missense_variant | 1/8 | ENST00000167586.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KRT14 | ENST00000167586.7 | c.374G>T | p.Arg125Leu | missense_variant | 1/8 | 1 | NM_000526.5 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 34
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:2Other:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Apr 07, 2022 | This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg125 amino acid residue in KRT14. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1717157, 16098032). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt KRT14 protein function. ClinVar contains an entry for this variant (Variation ID: 66349). This missense change has been observed in individual(s) with autosomal dominant epidermolysis bullosa simplex (PMID: 19854623, 31772641). In at least one individual the variant was observed to be de novo. This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 125 of the KRT14 protein (p.Arg125Leu). - |
not provided, no classification provided | literature only | Epithelial Biology; Institute of Medical Biology, Singapore | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Aug 26, 2022 | Located in the highly conserved helix initiation motif of the alpha-helical rod domain, which is intolerant to change; variants in this motif interfere with proper keratin intermediate filament assembly and function, resulting in skin fragility and/or hyperkeratosis (Chamcheu et al., 2011); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 20060687, 26432462, 31772641, 32484238, 19854623, 21176769) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at