rs118203937
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2PM5PP3_StrongPP5_Very_Strong
The NM_173483.4(CYP4F22):c.728G>A(p.Arg243His) variant causes a missense change. The variant allele was found at a frequency of 0.0000223 in 1,614,168 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R243C) has been classified as Likely 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.728G>A | p.Arg243His | missense_variant | 8/14 | ENST00000269703.8 | |
CYP4F22 | XM_011527692.3 | c.728G>A | p.Arg243His | missense_variant | 9/15 | ||
CYP4F22 | XM_011527693.3 | c.728G>A | p.Arg243His | missense_variant | 8/14 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CYP4F22 | ENST00000269703.8 | c.728G>A | p.Arg243His | missense_variant | 8/14 | 2 | NM_173483.4 | P1 | |
CYP4F22 | ENST00000601005.2 | c.728G>A | p.Arg243His | missense_variant | 6/12 | 5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152164Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000358 AC: 9AN: 251406Hom.: 0 AF XY: 0.0000368 AC XY: 5AN XY: 135910
GnomAD4 exome AF: 0.0000219 AC: 32AN: 1461886Hom.: 0 Cov.: 32 AF XY: 0.0000220 AC XY: 16AN XY: 727246
GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 152282Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3AN XY: 74472
ClinVar
Submissions by phenotype
Autosomal recessive congenital ichthyosis 5 Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Mar 23, 2022 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Mar 01, 2006 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Institute for Human Genetics, University Medical Center Freiburg | Apr 23, 2018 | - - |
Lamellar ichthyosis Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 30, 2021 | Variant summary: CYP4F22 c.728G>A (p.Arg243His) 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 3.6e-05 in 251406 control chromosomes. c.728G>A has been reported in the literature as a homozygous or compound heterozygous in multiple well phenotyped and comprehensively genotyped individuals affected with Autosomal Recessive Congenital Ichthyosis/Lamellar Ichthyosis (example, Lefevre_2006, Noguera-Morel_2016, Fakhro_2019, Esperon-Moldes_2020). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at