rs118203935

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_173483.4(CYP4F22):c.1303C>T(p.His435Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.000108 in 1,613,904 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 (★★).

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

CYP4F22
NM_173483.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 5.45

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.987

PP5

Variant 19-15549170-C-T is Pathogenic according to our data. Variant chr19-15549170-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 909.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-15549170-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
CYP4F22	NM_173483.4 linkuse as main transcript	c.1303C>T	p.His435Tyr	missense_variant	12/14	ENST00000269703.8
CYP4F22	XM_011527692.3 linkuse as main transcript	c.1303C>T	p.His435Tyr	missense_variant	13/15
CYP4F22	XM_011527693.3 linkuse as main transcript	c.1303C>T	p.His435Tyr	missense_variant	12/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP4F22	ENST00000269703.8 linkuse as main transcript	c.1303C>T	p.His435Tyr	missense_variant	12/14	2	NM_173483.4	P1
CYP4F22	ENST00000601005.2 linkuse as main transcript	c.1303C>T	p.His435Tyr	missense_variant	10/12	5		P1

Frequencies

GnomAD3 genomes

AF:

0.0000724

AC:

AN:

152038

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000725

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000656

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000557

AC:

AN:

251446

Hom.:

AF XY:

0.0000662

AC XY:

AN XY:

135904

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000116

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:

0.0000791

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000112

AC:

163

AN:

1461866

Hom.:

Cov.:

AF XY:

0.000125

AC XY:

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000894

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:

0.000134

Gnomad4 OTH exome

AF:

0.000149

GnomAD4 genome

AF:

0.0000724

AC:

AN:

152038

Hom.:

Cov.:

AF XY:

0.0000673

AC XY:

AN XY:

74262

show subpopulations

Gnomad4 AFR

AF:

0.0000725

Gnomad4 AMR

AF:

0.0000656

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000103

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000666

Hom.:

Bravo

AF:

0.0000869

ExAC

AF:

0.0000659

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000178

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autosomal recessive congenital ichthyosis 5

Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 12, 2019	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 24, 2020	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 01, 2006	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Feb 23, 2023	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.005%). Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.82; 3Cnet: 0.85). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000000909). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 16436457). The variant has been reported to co-segregate with the disease in at least one similarly affected relative/individual in the same family or similarly affected unrelated family (PMID: 16436457). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, no assertion criteria provided	clinical testing	Institute for Human Genetics, University Medical Center Freiburg	Apr 23, 2018	- -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Sep 01, 2021	This sequence change replaces histidine with tyrosine at codon 435 of the CYP4F22 protein (p.His435Tyr). The histidine residue is highly conserved and there is a moderate physicochemical difference between histidine and tyrosine. This variant is present in population databases (rs118203935, ExAC 0.01%). This missense change has been observed in individuals with non-syndromic autosomal recessive congenital ichthyosis (PMID: 16436457, 26646773). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 909). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 01, 2021	Published functional studies demonstrated that protein activity decreased significantly compared to wild-type protein activity (Ohno et al., 2015); This variant is associated with the following publications: (PMID: 32069299, 27535533, 31130284, 26646773, 16436457, 26056268) -

Lamellar ichthyosis

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Aug 24, 2021

Variant summary: CYP4F22 c.1303C>T (p.His435Tyr) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.6e-05 in 251446 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in CYP4F22 causing Lamellar Ichthyosis (5.6e-05 vs 0.00071), allowing no conclusion about variant significance. c.1303C>T has been reported in the literature in numerous individuals affected with Lamellar Ichthyosis, including segregating in multiple families (eg. Lefevre_2006, Esperon-Moldes_2020, etc). Functional studies have shown the variant result in significantly decreased omega-hydroxylase activity compared to wild-type (Ohno_2015). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.85

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Pathogenic

0.29

Cadd

Pathogenic

Dann

Uncertain

1.0

DEOGEN2

Uncertain

0.47

T;T

Eigen

Pathogenic

0.88

Eigen_PC

Pathogenic

0.79

FATHMM_MKL

Pathogenic

0.99

M_CAP

Benign

0.077

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Uncertain

0.49

MutationAssessor

Pathogenic

4.3

H;H

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.66

PROVEAN

Pathogenic

-5.4

D;.

REVEL

Pathogenic

0.82

Sift

Pathogenic

0.0

D;.

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;D

Vest4

0.97

MutPred

0.97

Loss of disorder (P = 0.0942);Loss of disorder (P = 0.0942);

MVP

0.83

MPC

0.89

ClinPred

0.99

GERP RS

4.8

Varity_R

0.95

gMVP

0.94

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over