rs531800013
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_173483.4(CYP4F22):c.59dup(p.Ile21HisfsTer59) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000131 in 1,613,978 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Genomes: 𝑓 0.000092 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00014 ( 0 hom. )
Consequence
CYP4F22
NM_173483.4 frameshift
NM_173483.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 3.01
Genes affected
CYP4F22 (HGNC:26820): (cytochrome P450 family 4 subfamily F member 22) This gene encodes a member of the cytochrome P450 superfamily of enzymes. The cytochrome P450 proteins are monooxygenases which catalyze many reactions involved in drug metabolism and synthesis of cholesterol, steroids and other lipids. This gene is part of a cluster of cytochrome P450 genes on chromosome 19 and encodes an enzyme thought to play a role in the 12(R)-lipoxygenase pathway. Mutations in this gene are the cause of ichthyosis lamellar type 3. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
?
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 34 pathogenic variants in the truncated region.
PM2
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Very rare variant in population databases, with high coverage;
PP5
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Variant 19-15525394-C-CG is Pathogenic according to our data. Variant chr19-15525394-C-CG is described in ClinVar as [Pathogenic]. Clinvar id is 279799.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CYP4F22 | NM_173483.4 | c.59dup | p.Ile21HisfsTer59 | frameshift_variant | 3/14 | ENST00000269703.8 | |
CYP4F22 | XM_011527692.3 | c.59dup | p.Ile21HisfsTer59 | frameshift_variant | 4/15 | ||
CYP4F22 | XM_011527693.3 | c.59dup | p.Ile21HisfsTer59 | frameshift_variant | 3/14 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CYP4F22 | ENST00000269703.8 | c.59dup | p.Ile21HisfsTer59 | frameshift_variant | 3/14 | 2 | NM_173483.4 | P1 | |
CYP4F22 | ENST00000601005.2 | c.59dup | p.Ile21HisfsTer59 | frameshift_variant | 1/12 | 5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000920 AC: 14AN: 152168Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000796 AC: 20AN: 251334Hom.: 0 AF XY: 0.0000662 AC XY: 9AN XY: 135854
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GnomAD4 exome AF: 0.000135 AC: 198AN: 1461810Hom.: 0 Cov.: 32 AF XY: 0.000111 AC XY: 81AN XY: 727226
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GnomAD4 genome ? AF: 0.0000920 AC: 14AN: 152168Hom.: 0 Cov.: 32 AF XY: 0.0000942 AC XY: 7AN XY: 74330
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Dec 09, 2019 | Identified in additional unrelated patients with congenital ichthyosis in the published literature (Pigg et al., 2016; Sitek et al., 2018); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 31046801, 27025581, 25998749, 29444371, 31168818, 31589614) - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Apr 01, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 20, 2022 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 279799). This premature translational stop signal has been observed in individuals with autosomal recessive congenital ichthyosis (PMID: 25998749, 27025581). This variant is present in population databases (rs531800013, gnomAD 0.02%). This sequence change creates a premature translational stop signal (p.Ile21Hisfs*59) in the CYP4F22 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CYP4F22 are known to be pathogenic (PMID: 16436457, 24397709, 26762237). - |
Autosomal recessive congenital ichthyosis 5 Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Institute for Human Genetics, University Medical Center Freiburg | Apr 23, 2018 | - - |
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at