dbSNP rs1425964436: CYP4F22:p.Arg515His (chr19-15551419-G-A) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_173483.4(CYP4F22):c.1544G>A(p.Arg515His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000693 in 1,442,890 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. R515L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

CYP4F22
NM_173483.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 8.77

Publications

0 publications found

Variant links:

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

CYP4F22 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.939

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP4F22	NM_173483.4	MANE Select	c.1544G>A	p.Arg515His	missense	Exon 14 of 14	NP_775754.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP4F22	ENST00000269703.8	TSL:2 MANE Select	c.1544G>A	p.Arg515His	missense	Exon 14 of 14	ENSP00000269703.1
	CYP4F22	ENST00000601005.2	TSL:5	c.1544G>A	p.Arg515His	missense	Exon 12 of 12	ENSP00000469866.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000468

AC:

AN:

213856

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000106

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.93e-7

AC:

AN:

1442890

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

716294

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32882

American (AMR)

AF:

0.00

AC:

AN:

42128

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25744

East Asian (EAS)

AF:

0.00

AC:

AN:

38348

South Asian (SAS)

AF:

0.00

AC:

AN:

83448

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51842

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5746

European-Non Finnish (NFE)

AF:

9.06e-7

AC:

AN:

1103168

Other (OTH)

AF:

0.00

AC:

AN:

59584

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000508

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.44

BayesDel_addAF

Pathogenic

0.24

BayesDel_noAF

Uncertain

0.11

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.30

Eigen

Pathogenic

0.73

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.97

M_CAP

Benign

0.082

MetaRNN

Pathogenic

0.94

MetaSVM

Uncertain

0.16

MutationAssessor

Pathogenic

3.3

PhyloP100

8.8

PrimateAI

Uncertain

0.73

PROVEAN

Pathogenic

-4.5

REVEL

Pathogenic

0.76

Sift

Uncertain

0.018

Sift4G

Uncertain

0.017

Polyphen

1.0

Vest4

0.75

MutPred

0.79

Loss of MoRF binding (P = 0.0075)

MVP

0.85

MPC

0.93

ClinPred

0.99

GERP RS

4.6

Varity_R

0.59

gMVP

0.83

Mutation Taster

=42/58

disease causing

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over