rs57837128
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_006121.4(KRT1):c.1436T>C(p.Ile479Thr) variant causes a missense 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I479F) has been classified as Pathogenic.
Frequency
Consequence
NM_006121.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KRT1 | NM_006121.4 | c.1436T>C | p.Ile479Thr | missense_variant | 7/9 | ENST00000252244.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KRT1 | ENST00000252244.3 | c.1436T>C | p.Ile479Thr | missense_variant | 7/9 | 1 | NM_006121.4 | P1 | |
KRT1 | ENST00000548765.1 | n.510T>C | non_coding_transcript_exon_variant | 3/4 | 2 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 30
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:2Other:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 03, 2023 | This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 479 of the KRT1 protein (p.Ile479Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with KRT1-related conditions (PMID: 10053007, 15214894, 22250628, 30152556). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 15911). 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 KRT1 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 24, 2023 | Located in the highly conserved helix termination 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 (PMID: 21176769, 21271994, 26176760); Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 10688370, 27421141, 27617465, 32588446, 10053007, 26581228, 26945532, 23623204, 21271994, 25904304, 30152556, 34188299, 32666929, 21176769, 26176760, 36656063, 22250628, 15214894) - |
not provided, no classification provided | literature only | Epithelial Biology; Institute of Medical Biology, Singapore | - | - - |
Ichthyosis, annular epidermolytic, 2 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Mar 01, 1999 | - - |
Annular epidermolytic ichthyosis Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | - | The missense variant p.I479T in KRT1 (NM_006121.4) has been previously reported in patients with cyclic ichthyosis with epidermolytic hyperkeratosis as well as in patients with epidermolytic palmoplantar keratoderma ( Hotz et al., 2016; TerronKwiatkowski et al., 2004). The variant has been submitted to ClinVar as Pathogenic.No functional studies have been performed. The p.I479T variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. The p.I479T missense variant is predicted to be damaging by both SIFT and PolyPhen2. The isoleucine residue at codon 479 of KRT1 is conserved in all mammalian species. The nucleotide c.1436 in KRT1 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Likely Pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at