19-15525335-G-A

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 14P and 1B. PVS1 PM2 PP3_Strong BS1_Supporting

The NM_173483.4(CYP4F22):c.-1-1G>A variant causes a splice acceptor change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000211 in 1,613,098 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: CYP4F22 NM_173483.4 splice_acceptor
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 3.53

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.

• PVS1: Splicing variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 6.8, offset of 1, new splice context is: tgaccctgtgtgtccccaAGatg. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• BS1: Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.0000205 (30/1460772) while in subpopulation EAS AF= 0.000731 (29/39686). AF 95% confidence interval is 0.000522. There are 0 homozygotes in gnomad4_exome. There are 16 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	UniProt
CYP4F22	NM_173483.4	c.-1-1G>A		splice_acceptor_variant		ENST00000269703.8
CYP4F22	XM_011527692.3	c.-1-1G>A		splice_acceptor_variant
CYP4F22	XM_011527693.3	c.-1-1G>A		splice_acceptor_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP4F22	ENST00000269703.8	c.-1-1G>A		splice_acceptor_variant		2	NM_173483.4	P1
CYP4F22	ENST00000601005.2	c.-2G>A		5_prime_UTR_variant	1/12	5		P1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152208 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000769

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000920 AC: 23 AN: 250046 Hom.: 0 AF XY: 0.0000887 AC XY: 12 AN XY: 135276

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00120

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.0000205 AC: 30 AN: 1460772 Hom.: 0 Cov.: 32 AF XY: 0.0000220 AC XY: 16 AN XY: 726732

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000731

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152326 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74486

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000771

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000422 Hom.: 0

Bravo AF: 0.0000491

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Apr 17, 2023

Variant summary: CYP4F22 c.-1-1G>A is located in a canonical splice-site in the 5' UTR and is predicted to affect mRNA splicing which might alter the protein sequence due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: four predict the variant abolishes a 3' splicing acceptor site, and three predict the variant strengthens a cryptic 3' acceptor site one nucleotide downstream of the original splice site, but still upstream from the protein coding sequence, thus it is not predicted to result in a sequence change at the protein level, if utilized for splicing. On the other hand, this variant also alters a conserved position in the Kozak consensus sequence, therefore might affect the efficiency of the initiation of protein translation (PMID: 12459250). However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 9.2e-05 in 250046 control chromosomes, predominantly at a frequency of 0.0012 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 1.7 fold of the estimated maximal expected allele frequency for a pathogenic variant in CYP4F22 causing Lamellar Ichthyosis phenotype (0.00071), suggesting that the variant might be a benign polymorphism found primarily in populations of East Asian origin. To our knowledge, no occurrence of c.-1-1G>A in individuals affected with Lamellar Ichthyosis and no experimental evidence demonstrating its impact on protein function have been reported. One ClinVar submitter (evaluation after 2014) classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -

Autosomal recessive congenital ichthyosis 5 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Nov 26, 2018

The CYP4F22 c.-1-1G>A variant occurs in a canonical splice site (acceptor) and is therefore predicted to disrupt or distort the normal gene product. A literature search was performed for the gene and cDNA change. No publications were found based on this search. This variant is found at a frequency of 0.001113 in the East Asian population of the Genome Aggregation Database. Based on the potential impact of splice site (acceptor) variants, the c.-1-1G>A variant is classified as a variant of unknown significance but suspicious for pathogenicity for congenital ichthyosis. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Uncertain	0.020
Cadd	Pathogenic	33
Dann	Benign	0.92

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.88		Position offset: 2
DS_AL_spliceai		0.99		Position offset: 1

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

Publications

LitVar

Other links and lift over

dbSNP: rs200464692; hg19: chr19-15636146;