dbSNP rs118091316: CYP4F22:p.Phe59Leu (chr19-15525513-C-A) – ACMG Classification: Pathogenic (14 pts)

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PS1_Very_StrongPM2PP3_Strong

The NM_173483.4(CYP4F22):c.177C>A(p.Phe59Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,876 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 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)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

CYP4F22
NM_173483.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.06

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, Labcorp Genetics (formerly Invitae)
lamellar ichthyosis
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

CYP4F22 links:

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ACMG classification

Classification was made for transcript

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, 0.962

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.177C>A	p.Phe59Leu	missense	Exon 3 of 14	NP_775754.2	Q6NT55

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CYP4F22	ENST00000269703.8	TSL:2 MANE Select	c.177C>A	p.Phe59Leu	missense	Exon 3 of 14	ENSP00000269703.1	Q6NT55
CYP4F22	ENST00000601005.2	TSL:5	c.177C>A	p.Phe59Leu	missense	Exon 1 of 12	ENSP00000469866.1	Q6NT55
CYP4F22	ENST00000894419.1		c.177C>A	p.Phe59Leu	missense	Exon 4 of 15	ENSP00000564478.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1459876

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726336

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33476

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51634

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5740

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111862

Other (OTH)

AF:

0.00

AC:

AN:

60356

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.96

BayesDel_addAF

Pathogenic

0.36

BayesDel_noAF

Pathogenic

0.28

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.33

Eigen

Uncertain

0.24

Eigen_PC

Uncertain

0.25

FATHMM_MKL

Uncertain

0.85

LIST_S2

Uncertain

0.95

M_CAP

Uncertain

0.12

MetaRNN

Pathogenic

0.96

MetaSVM

Uncertain

0.23

MutationAssessor

Uncertain

2.7

PhyloP100

2.1

PrimateAI

Uncertain

0.57

PROVEAN

Pathogenic

-5.1

REVEL

Pathogenic

0.70

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.0060

Polyphen

1.0

Vest4

0.83

MutPred

0.83

Gain of catalytic residue at F59 (P = 0.0045)

MVP

0.94

MPC

0.87

ClinPred

1.0

GERP RS

3.8

PromoterAI

-0.011

Neutral

(source)

Varity_R

0.82

gMVP

0.68

Mutation Taster

=8/92

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over