19-15525511-T-C

Variant names:

• chr19-15525511-T-C
• NM_173483.4:c.175T>C
• CYP4F22 p.Phe59Leu

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PS1_Very_Strong PM2 PP3_Strong

The NM_173483.4(CYP4F22):​c.175T>C​(p.Phe59Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar. Synonymous variant affecting the same amino acid position (i.e. F59F) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CYP4F22 NM_173483.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.42
• Publications: 0 publications found

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, Labcorp Genetics (formerly Invitae)
• lamellar ichthyosis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 14 ACMG points.

• PS1: Transcript NM_173483.4 (CYP4F22) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.96

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_173483.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP4F22	NM_173483.4	MANE Select	c.175T>C	p.Phe59Leu	missense	Exon 3 of 14	NP_775754.2	Q6NT55

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP4F22	ENST00000269703.8	TSL:2 MANE Select	c.175T>C	p.Phe59Leu	missense	Exon 3 of 14	ENSP00000269703.1	Q6NT55
	CYP4F22	ENST00000601005.2	TSL:5	c.175T>C	p.Phe59Leu	missense	Exon 1 of 12	ENSP00000469866.1	Q6NT55
	CYP4F22	ENST00000894419.1		c.175T>C	p.Phe59Leu	missense	Exon 4 of 15	ENSP00000564478.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.33	T
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.095	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Uncertain	0.34	D
MutationAssessor	Uncertain	2.7	M
PhyloP100		4.4
PrimateAI	Uncertain	0.57	T
PROVEAN	Pathogenic	-5.1	D
REVEL	Pathogenic	0.80
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0060	D
PromoterAI		0.017	Neutral
Varity_R		0.75
gMVP		0.68
Mutation Taster		=62/38	polymorphism

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr19-15636322;