chr19-15540622-C-T

Position:

• chr19-15540622-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_173483.4(CYP4F22):​c.844C>T​(p.Arg282Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000103 in 1,461,874 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 Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: CYP4F22 NM_173483.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 0.264

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.929

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYP4F22	NM_173483.4	c.844C>T	p.Arg282Trp	missense_variant	8/14	ENST00000269703.8	NP_775754.2
CYP4F22	XM_011527692.3	c.844C>T	p.Arg282Trp	missense_variant	9/15		XP_011525994.1
CYP4F22	XM_011527693.3	c.844C>T	p.Arg282Trp	missense_variant	8/14		XP_011525995.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYP4F22	ENST00000269703.8	c.844C>T	p.Arg282Trp	missense_variant	8/14	2	NM_173483.4	ENSP00000269703	P1
CYP4F22	ENST00000601005.2	c.844C>T	p.Arg282Trp	missense_variant	6/12	5		ENSP00000469866	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251196 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135854

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000103 AC: 15 AN: 1461874 Hom.: 0 Cov.: 32 AF XY: 0.0000110 AC XY: 8 AN XY: 727240

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000809

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.000187 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Autosomal recessive congenital ichthyosis 5 Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 23, 2017	The CYP4F22 c.844C>T (p.Arg282Trp) variant has been reported in two studies and is found in a total of three patients with congenital ichthyosis (Buckova et al. 2015; Feng et al. 2017). In two siblings born to consanguinous parents, the p.Arg282Trp variant was detected in a homozygous state (Feng et al. 2017). One of the siblings was described to have a mild clinical presentation, while clinical features were not provided for the other. A third sibling in this family was described as clinically affected, but died in infancy due to infection and so was not tested. Family studies identified the p.Arg282Trp variant in a heterozygous state in the unaffected parents and an unaffected sister. Buckova et al. (2015) reported the p.Arg282Trp variant in a compound heterozygous state with another missense variant in a 4 year old child with pronounced scaling on the face, scalp and legs who was born with a collodion membrane. Functional studies and control data are unavailable for this variant, which is reported at a frequency of 0.00001 in the Total population of the Genome Aggregation Database. The p.Arg282Trp variant is therefore 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. -
Pathogenic, no assertion criteria provided	clinical testing	Institute for Human Genetics, University Medical Center Freiburg	Apr 23, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.67
BayesDel_addAF	Uncertain	0.012	T
BayesDel_noAF	Uncertain	-0.040
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.49	T;T
Eigen	Uncertain	0.23
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.93	.;D
M_CAP	Uncertain	0.20	D
MetaRNN	Pathogenic	0.93	D;D
MetaSVM	Uncertain	0.37	D
MutationAssessor	Pathogenic	4.0	H;H
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-7.7	D;.
REVEL	Uncertain	0.59
Sift	Uncertain	0.0030	D;.
Sift4G	Uncertain	0.0060	D;D
Polyphen		0.95	P;P
Vest4		0.95
MutPred		0.74		Loss of disorder (P = 0.0061);Loss of disorder (P = 0.0061);
MVP		0.87
MPC		0.85
ClinPred		0.94	D
GERP RS		3.0
Varity_R		0.92
gMVP		0.89

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: rs767352854; hg19: chr19-15651433; COSMIC: COSV54106743;