NM_173483.4:c.177C>G

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 12P and 1B. PP3_StrongPP5_Very_StrongBS1_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 Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

CYP4F22
NM_173483.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9

Conservation

PhyloP100: 2.06

Publications

9 publications found

Variant links:

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]

CYP4F22 Gene-Disease associations (from GenCC):

autosomal recessive congenital ichthyosis 5
Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp, PanelApp Australia, Labcorp Genetics (formerly Invitae)
lamellar ichthyosis
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

CYP4F22 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 11 ACMG points.

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 Pathogenic/Likely_pathogenic. ClinVar VariationId 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. GnomAdExome4 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 GnomAdExome4. There are 4 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP4F22	NM_173483.4 link	c.177C>G	p.Phe59Leu	missense_variant	Exon 3 of 14	ENST00000269703.8	NP_775754.2	Q6NT55
CYP4F22	XM_011527692.3 link	c.177C>G	p.Phe59Leu	missense_variant	Exon 4 of 15		XP_011525994.1	Q6NT55
CYP4F22	XM_011527693.3 link	c.177C>G	p.Phe59Leu	missense_variant	Exon 3 of 14		XP_011525995.1	Q6NT55

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP4F22	ENST00000269703.8 link	c.177C>G	p.Phe59Leu	missense_variant	Exon 3 of 14	2	NM_173483.4	ENSP00000269703.1		Q6NT55
CYP4F22	ENST00000601005.2 link	c.177C>G	p.Phe59Leu	missense_variant	Exon 1 of 12	5		ENSP00000469866.1		Q6NT55

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000400

AC:

AN:

249736

AF XY:

0.00000740

show subpopulations

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000884

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000479

AC:

AN:

1459876

Hom.:

Cov.:

AF XY:

0.00000551

AC XY:

AN XY:

726336

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33476

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51634

Middle Eastern (MID)

AF:

0.00122

AC:

AN:

5740

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111862

Other (OTH)

AF:

0.00

AC:

AN:

60356

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autosomal recessive congenital ichthyosis 5

Pathogenic:6

Jan 15, 2020

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -

Apr 23, 2018

Institute for Human Genetics, University Medical Center Freiburg

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jun 20, 2019

Hadassah Hebrew University Medical Center

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 17, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

Feb 05, 2020

Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

May 18, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Lamellar ichthyosis

Pathogenic:1

May 16, 2024

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

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Sep 12, 2024

PreventionGenetics, part of Exact Sciences

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

Feb 15, 2022

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

BayesDel_noAF

Pathogenic

0.28

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.33

T;T

Eigen

Uncertain

0.24

Eigen_PC

Uncertain

0.25

FATHMM_MKL

Uncertain

0.86

LIST_S2

Uncertain

0.95

.;D

M_CAP

Uncertain

0.097

MetaRNN

Pathogenic

0.96

D;D

MetaSVM

Uncertain

0.23

MutationAssessor

Uncertain

2.7

M;M

PhyloP100

2.1

PrimateAI

Uncertain

0.57

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

GERP RS

3.8

PromoterAI

-0.022

Neutral

(source)

Varity_R

0.82

gMVP

0.68

Mutation Taster

=8/92

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over