19-15525513-C-G

Position:

• chr19-15525513-C-G

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 14P and 1B. PM2 PP3_Strong PP5_Very_Strong BS1_Supporting

The NM_173483.4(CYP4F22):​c.177C>G​(p.Phe59Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,459,876 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 (★★). Synonymous variant affecting the same amino acid position (i.e. F59F) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: CYP4F22 NM_173483.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 2.06

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]

ACMG classification

Verdict is Pathogenic. Variant got 13 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.96
• PP5: Variant 19-15525513-C-G is Pathogenic according to our data. Variant chr19-15525513-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 560326.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00000479 (7/1459876) while in subpopulation MID AF= 0.00122 (7/5740). AF 95% confidence interval is 0.000572. There are 0 homozygotes in gnomad4_exome. There are 4 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYP4F22	NM_173483.4	c.177C>G	p.Phe59Leu	missense_variant	3/14	ENST00000269703.8	NP_775754.2
CYP4F22	XM_011527692.3	c.177C>G	p.Phe59Leu	missense_variant	4/15		XP_011525994.1
CYP4F22	XM_011527693.3	c.177C>G	p.Phe59Leu	missense_variant	3/14		XP_011525995.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYP4F22	ENST00000269703.8	c.177C>G	p.Phe59Leu	missense_variant	3/14	2	NM_173483.4	ENSP00000269703.1
CYP4F22	ENST00000601005.2	c.177C>G	p.Phe59Leu	missense_variant	1/12	5		ENSP00000469866.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000400 AC: 1 AN: 249736 Hom.: 0 AF XY: 0.00000740 AC XY: 1 AN XY: 135138

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000884

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1459876 Hom.: 0 Cov.: 32 AF XY: 0.00000551 AC XY: 4 AN XY: 726336

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive congenital ichthyosis 5 Pathogenic:6

Pathogenic, no assertion criteria provided	clinical testing	Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	Feb 05, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	May 18, 2024	- -
Pathogenic, no assertion criteria provided	clinical testing	Institute for Human Genetics, University Medical Center Freiburg	Apr 23, 2018	- -
Pathogenic, criteria provided, single submitter	research	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 17, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jan 15, 2020	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Hadassah Hebrew University Medical Center	Jun 20, 2019	- -

Lamellar ichthyosis Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

May 16, 2024

Variant summary: CYP4F22 c.177C>G (p.Phe59Leu) 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 4e-06 in 249736 control chromosomes. c.177C>G has been reported in the literature in the homozygous state in multiple individuals affected with Lamellar Ichthyosis (e.g. Lefevre_2006, Seidl-Philipp_2020, Mohamad_2021). These data indicate that the variant is very likely to be associated with disease. At least one functional study reports that the variant results in <20% activity compared to the wild-type protein (e.g. Ohno_2015). The following publications have been ascertained in the context of this evaluation (PMID: 16436457, 33786896, 26056268, 31642606). ClinVar contains an entry for this variant (Variation ID: 560326). Based on the evidence outlined above, the variant was classified as pathogenic. -

CYP4F22-related disorder Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 12, 2024

The CYP4F22 c.177C>G variant is predicted to result in the amino acid substitution p.Phe59Leu. This variant has been reported in the homozygous state in individuals with autosomal recessive congenital ichthyosis (Lefevre et al. 2006. PubMed ID: 16436457; Table S1, Monies et al. 2019. PubMed ID: 31130284; Table S2a, Seidl-Philipp et al. 2019. PubMed ID: 31642606; Table S2, Simpson et al. 2019. PubMed ID: 31168818). In vitro functional studies demonstrated that expression of this variant resulted in a decrease of omega-hydroxylase activity to <20% of the wild-type protein (Ohno et al. 2015. PubMed ID: 26056268). This variant is reported in 0.00088% of alleles in individuals of European (non-Finnish) descent in gnomAD, and is interpreted as pathogenic/likely pathogenic in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/560326/). This variant is interpreted as likely pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Feb 15, 2022

Published functional studies of F59L demonstrate a significant decrease of enzyme activity (Ohno et al., 2015); Not observed at a significant frequency 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: 31168818, 16436457, 31130284, 33067036, 26056268) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.33	T;T
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.95	.;D
M_CAP	Uncertain	0.097	D
MetaRNN	Pathogenic	0.96	D;D
MetaSVM	Uncertain	0.23	D
MutationAssessor	Uncertain	2.7	M;M
PrimateAI	Uncertain	0.57	T
PROVEAN	Pathogenic	-5.1	D;.
REVEL	Pathogenic	0.70
Sift	Uncertain	0.0020	D;.
Sift4G	Uncertain	0.0060	D;D
Polyphen		1.0	D;D
Vest4		0.83
MutPred		0.83		Gain of catalytic residue at F59 (P = 0.0045);Gain of catalytic residue at F59 (P = 0.0045);
MVP		0.94
MPC		0.87
ClinPred		1.0	D
GERP RS		3.8
Varity_R		0.82
gMVP		0.68

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs118091316; hg19: chr19-15636324;