rs369811073

Variant names:

• chr19-15529728-G-A
• rs369811073
• NM_173483.4:c.242G>A

Your query was ambiguous. Multiple possible variants found:

• chr19-15529728-G-A
• chr19-15529728-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP3 PP5_Moderate

The NM_173483.4(CYP4F22):​c.242G>A​(p.Gly81Asp) variant causes a missense change. The variant allele was found at a frequency of 0.0000041 in 1,461,886 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: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: CYP4F22 NM_173483.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• 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 Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.775
• PP5: Variant 19-15529728-G-A is Pathogenic according to our data. Variant chr19-15529728-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 560306.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP4F22	NM_173483.4	c.242G>A	p.Gly81Asp	missense_variant	Exon 4 of 14	ENST00000269703.8	NP_775754.2
CYP4F22	XM_011527692.3	c.242G>A	p.Gly81Asp	missense_variant	Exon 5 of 15		XP_011525994.1
CYP4F22	XM_011527693.3	c.242G>A	p.Gly81Asp	missense_variant	Exon 4 of 14		XP_011525995.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP4F22	ENST00000269703.8	c.242G>A	p.Gly81Asp	missense_variant	Exon 4 of 14	2	NM_173483.4	ENSP00000269703.1
CYP4F22	ENST00000601005.2	c.242G>A	p.Gly81Asp	missense_variant	Exon 2 of 12	5		ENSP00000469866.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461886 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727242

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: 0.00000540

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Autosomal recessive congenital ichthyosis 5 Pathogenic:1

Apr 23, 2018

Institute for Human Genetics, University Medical Center Freiburg

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Lamellar ichthyosis Pathogenic:1

Feb 17, 2025

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.242G>A (p.Gly81Asp) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251438 control chromosomes. c.242G>A has been reported in the literature in individuals affected with Lamellar Ichthyosis (e.g. Hotz_2018, Diociaiuti_2024). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function and found that the variant results in <10% of WT enzyme activity (Nohara_2021). The following publications have been ascertained in the context of this evaluation (PMID: 30011118, 38588653, 33067036). ClinVar contains an entry for this variant (Variation ID: 560306). 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	0.80
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.29	T;T
Eigen	Benign	-0.093
Eigen_PC	Benign	0.017
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.75	.;T
M_CAP	Benign	0.083	D
MetaRNN	Pathogenic	0.77	D;D
MetaSVM	Uncertain	0.65	D
MutationAssessor	Uncertain	2.1	M;M
PrimateAI	Uncertain	0.58	T
PROVEAN	Pathogenic	-5.3	D;.
REVEL	Uncertain	0.64
Sift	Benign	0.15	T;.
Sift4G	Benign	0.15	T;T
Polyphen		0.23	B;B
Vest4		0.71
MutPred		0.45		Loss of ubiquitination at K86 (P = 0.0787);Loss of ubiquitination at K86 (P = 0.0787);
MVP		0.91
MPC		0.94
ClinPred		0.99	D
GERP RS		5.4
Varity_R		0.72
gMVP		0.92

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs369811073; hg19: chr19-15640539;