rs768098854
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2PM5PP3_StrongPP5_Very_Strong
The NM_173483.4(CYP4F22):c.727C>T(p.Arg243Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000285 in 1,614,044 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R243H) has been classified as Pathogenic.
Frequency
Consequence
NM_173483.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CYP4F22 | NM_173483.4 | c.727C>T | p.Arg243Cys | missense_variant | 8/14 | ENST00000269703.8 | |
CYP4F22 | XM_011527692.3 | c.727C>T | p.Arg243Cys | missense_variant | 9/15 | ||
CYP4F22 | XM_011527693.3 | c.727C>T | p.Arg243Cys | missense_variant | 8/14 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CYP4F22 | ENST00000269703.8 | c.727C>T | p.Arg243Cys | missense_variant | 8/14 | 2 | NM_173483.4 | P1 | |
CYP4F22 | ENST00000601005.2 | c.727C>T | p.Arg243Cys | missense_variant | 6/12 | 5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152158Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000239 AC: 6AN: 251400Hom.: 0 AF XY: 0.0000294 AC XY: 4AN XY: 135900
GnomAD4 exome AF: 0.0000301 AC: 44AN: 1461886Hom.: 0 Cov.: 32 AF XY: 0.0000316 AC XY: 23AN XY: 727244
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152158Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74336
ClinVar
Submissions by phenotype
Lamellar ichthyosis Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 21, 2023 | Variant summary: CYP4F22 c.727C>T (p.Arg243Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 251400 control chromosomes (gnomAD). c.727C>T has been reported in the literature in bi-allelic individuals affected with Lamellar Ichthyosis (example: Pigg_2016). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A different variant affecting the same amino acid (p.R243H) is classified pathogenic by our lab and in ClinVar. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
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 | - - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Feb 04, 2021 | In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 30011118, 27025581) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at