rs118203935

Positions:

• chr19-15549170-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_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
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 5.45

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 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	Protein	UniProt
CYP4F22	NM_173483.4	c.1303C>T	p.His435Tyr	missense_variant	12/14	ENST00000269703.8	NP_775754.2
CYP4F22	XM_011527692.3	c.1303C>T	p.His435Tyr	missense_variant	13/15		XP_011525994.1
CYP4F22	XM_011527693.3	c.1303C>T	p.His435Tyr	missense_variant	12/14		XP_011525995.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYP4F22	ENST00000269703.8	c.1303C>T	p.His435Tyr	missense_variant	12/14	2	NM_173483.4	ENSP00000269703.1
CYP4F22	ENST00000601005.2	c.1303C>T	p.His435Tyr	missense_variant	10/12	5		ENSP00000469866.1

Frequencies

GnomAD3 genomes AF: 0.0000724 AC: 11 AN: 152038 Hom.: 0 Cov.: 31

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: 14 AN: 251446 Hom.: 0 AF XY: 0.0000662 AC XY: 9 AN XY: 135904

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.: 0 Cov.: 31 AF XY: 0.000125 AC XY: 91 AN XY: 727242

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: 11 AN: 152038 Hom.: 0 Cov.: 31 AF XY: 0.0000673 AC XY: 5 AN XY: 74262

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.: 0

Bravo AF: 0.0000869

ExAC AF: 0.0000659 AC: 8

EpiCase AF: 0.000109

EpiControl AF: 0.000178

ClinVar

Significance: 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	Institute for Human Genetics, University Medical Center Freiburg	Apr 23, 2018	- -
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	literature only	OMIM	Mar 01, 2006	- -
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, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Sep 22, 2024	- -

not provided Pathogenic:2

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) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	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. -

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	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.47	T;T
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	.;D
M_CAP	Benign	0.077	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Uncertain	0.49	D
MutationAssessor	Pathogenic	4.3	H;H
PrimateAI	Uncertain	0.66	T
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	D
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

Other links and lift over

dbSNP: rs118203935; hg19: chr19-15659981;