rs199892192
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Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1PM2
The NM_173483.4(CYP4F22):c.667C>T(p.Gln223Ter) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000514 in 1,613,984 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 Uncertain significance (★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.00013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000043 ( 0 hom. )
Consequence
CYP4F22
NM_173483.4 stop_gained
NM_173483.4 stop_gained
Scores
5
1
1
Clinical Significance
Conservation
PhyloP100: 7.24
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 10 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CYP4F22 | NM_173483.4 | c.667C>T | p.Gln223Ter | stop_gained | 7/14 | ENST00000269703.8 | |
CYP4F22 | XM_011527692.3 | c.667C>T | p.Gln223Ter | stop_gained | 8/15 | ||
CYP4F22 | XM_011527693.3 | c.667C>T | p.Gln223Ter | stop_gained | 7/14 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CYP4F22 | ENST00000269703.8 | c.667C>T | p.Gln223Ter | stop_gained | 7/14 | 2 | NM_173483.4 | P1 | |
CYP4F22 | ENST00000601005.2 | c.667C>T | p.Gln223Ter | stop_gained | 5/12 | 5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000131 AC: 20AN: 152132Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000111 AC: 28AN: 251456Hom.: 0 AF XY: 0.0000736 AC XY: 10AN XY: 135902
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GnomAD4 exome AF: 0.0000431 AC: 63AN: 1461852Hom.: 0 Cov.: 34 AF XY: 0.0000385 AC XY: 28AN XY: 727230
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GnomAD4 genome ? AF: 0.000131 AC: 20AN: 152132Hom.: 0 Cov.: 32 AF XY: 0.000269 AC XY: 20AN XY: 74314
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ClinVar
Significance: Uncertain significance
Submissions summary: Pathogenic:1Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Autosomal recessive congenital ichthyosis 5 Pathogenic:1Uncertain:1
Pathogenic, no assertion criteria provided | clinical testing | Institute for Human Genetics, University Medical Center Freiburg | Apr 23, 2018 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | The CYP4F22 c.667C>T (p.Gln223Ter) variant is a stop-gained variant and has been reported in a single study in a homozygous state in one individual with congenital ichthyosis (Hellstrom Pigg et al. 2016). Control data are not available for the p.Gln223Ter variant which is reported at a frequency of 0.00121 in the European (non-Finnish) population of the Exome Aggregation Consortium. Due to the potential impact of stop-gained variants and evidence from the literature, the p.Gln223Ter variant is classified as a variant of unknown significance, but suspicious for pathogenicity for congenital ichthyosis. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. - |
Computational scores
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Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
MutationTaster
Benign
A
Vest4
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Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at