rs1555730246

Variant names:

• chr19-15548182-T-C
• rs1555730246
• NM_173483.4:c.1211T>C

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1 PM2 PP3

The NM_173483.4(CYP4F22):​c.1211T>C​(p.Leu404Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: CYP4F22 NM_173483.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.22
• 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, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• lamellar ichthyosis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_173483.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.755

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP4F22	NM_173483.4	c.1211T>C	p.Leu404Pro	missense_variant	Exon 11 of 14	ENST00000269703.8	NP_775754.2
CYP4F22	XM_011527692.3	c.1211T>C	p.Leu404Pro	missense_variant	Exon 12 of 15		XP_011525994.1
CYP4F22	XM_011527693.3	c.1211T>C	p.Leu404Pro	missense_variant	Exon 11 of 14		XP_011525995.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP4F22	ENST00000269703.8	c.1211T>C	p.Leu404Pro	missense_variant	Exon 11 of 14	2	NM_173483.4	ENSP00000269703.1
CYP4F22	ENST00000601005.2	c.1211T>C	p.Leu404Pro	missense_variant	Exon 9 of 12	5		ENSP00000469866.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Atopic eczema;C0020757:Ichthyosis Uncertain:1

Jan 01, 2017

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
CADD	Benign	19
DANN	Benign	0.94
DEOGEN2	Benign	0.095	T;T
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.64
FATHMM_MKL	Benign	0.061	N
LIST_S2	Benign	0.75	.;T
M_CAP	Benign	0.047	D
MetaRNN	Pathogenic	0.75	D;D
MetaSVM	Benign	-0.88	T
MutationAssessor	Uncertain	2.6	M;M
PhyloP100		1.2
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-2.4	N;.
REVEL	Uncertain	0.39
Sift	Benign	0.17	T;.
Sift4G	Benign	0.28	T;T
Polyphen		0.0020	B;B
Vest4		0.88
MutPred		0.58		Gain of disorder (P = 0.0123);Gain of disorder (P = 0.0123);
MVP		0.57
MPC		1.0
ClinPred		0.33	T
GERP RS		4.2
Varity_R		0.68
gMVP		0.88
Mutation Taster		=78/22	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs1555730246; hg19: chr19-15658993;