rs572278771

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBS1BS2

The NM_173483.4(CYP4F22):c.712G>A(p.Ala238Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000368 in 1,614,118 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00018 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00039 ( 5 hom. )

Consequence

CYP4F22
NM_173483.4 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts P:1U:1B:2

Conservation

PhyloP100: 0.586

Publications

1 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: Benign. The variant received -18 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 5 uncertain in NM_173483.4

BP4

Computational evidence support a benign effect (MetaRNN=0.017583579).

BP6

Variant 19-15540490-G-A is Benign according to our data. Variant chr19-15540490-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 560335.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000184 (28/152232) while in subpopulation SAS AF = 0.00477 (23/4818). AF 95% confidence interval is 0.00326. There are 0 homozygotes in GnomAd4. There are 18 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP4F22	NM_173483.4 link	c.712G>A	p.Ala238Thr	missense_variant	Exon 8 of 14	ENST00000269703.8	NP_775754.2	Q6NT55
CYP4F22	XM_011527692.3 link	c.712G>A	p.Ala238Thr	missense_variant	Exon 9 of 15		XP_011525994.1	Q6NT55
CYP4F22	XM_011527693.3 link	c.712G>A	p.Ala238Thr	missense_variant	Exon 8 of 14		XP_011525995.1	Q6NT55

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP4F22	ENST00000269703.8 link	c.712G>A	p.Ala238Thr	missense_variant	Exon 8 of 14	2	NM_173483.4	ENSP00000269703.1		Q6NT55
CYP4F22	ENST00000601005.2 link	c.712G>A	p.Ala238Thr	missense_variant	Exon 6 of 12	5		ENSP00000469866.1		Q6NT55

Frequencies

GnomAD3 genomes

AF:

0.000184

AC:

AN:

152114

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00477

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000780

AC:

196

AN:

251372

AF XY:

0.00107

show subpopulations

Gnomad AFR exome

AF:

0.0000615

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:

0.00

Gnomad OTH exome

AF:

0.000815

GnomAD4 exome

AF:

0.000387

AC:

566

AN:

1461886

Hom.:

Cov.:

AF XY:

0.000562

AC XY:

409

AN XY:

727242

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00612

AC:

528

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000540

AC:

AN:

1112010

Other (OTH)

AF:

0.000513

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

136

182

227

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

AF:

0.000184

AC:

AN:

152232

Hom.:

Cov.:

AF XY:

0.000242

AC XY:

AN XY:

74428

show subpopulations

African (AFR)

AF:

0.0000722

AC:

AN:

41548

American (AMR)

AF:

0.0000654

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00477

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10598

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68014

Other (OTH)

AF:

0.00

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.520

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.0000673

Hom.:

Bravo

AF:

0.0000680

ExAC

AF:

0.000873

AC:

106

Asia WGS

AF:

0.00173

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Pathogenic:1Uncertain:1Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autosomal recessive congenital ichthyosis 5

Pathogenic:1Uncertain:1

Jul 31, 2018

Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Apr 23, 2018

Institute for Human Genetics, University Medical Center Freiburg

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not specified

Benign:1

Sep 03, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: CYP4F22 c.712G>A (p.Ala238Thr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00078 in 251372 control chromosomes (gnomAD), predominantly at a frequency of 0.0062 within the South Asian subpopulation in the gnomAD database. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 9 fold of the estimated maximal expected allele frequency for a pathogenic variant in CYP4F22 causing Lamellar Ichthyosis (0.00071), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. c.712G>A has been reported in the literature in individuals affected with Congenital Ichthyosis (Scott_2013, Hotz_2018), however these reports do not provide unequivocal conclusions about association of the variant with disease. When assayed for -hydroxylase activity in a cell-based assay, the variant was found to have comparable activity as WT (Nohara_2021). Three ClinVar submitters have assessed the variant since 2014 without evidence for independent evaluation: one classified the variant as pathogenic, one as uncertain significance, and one as likely benign. Based on the evidence outlined above, the variant was classified as likely benign. -

not provided

Benign:1

Mar 13, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.086

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.13

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.049

T;T

Eigen

Benign

-0.58

Eigen_PC

Benign

-0.62

FATHMM_MKL

Benign

0.093

LIST_S2

Uncertain

0.88

.;D

M_CAP

Uncertain

0.10

MetaRNN

Benign

0.018

T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

0.79

N;N

PhyloP100

0.59

PrimateAI

Benign

0.46

PROVEAN

Benign

-1.7

N;.

REVEL

Uncertain

0.29

Sift

Benign

0.26

T;.

Sift4G

Benign

0.42

T;T

Polyphen

0.54

P;P

Vest4

0.65

MutPred

0.24

Loss of helix (P = 0.1706);Loss of helix (P = 0.1706);

MVP

0.63

MPC

0.44

ClinPred

0.074

GERP RS

4.3

Varity_R

0.10

gMVP

0.25

Mutation Taster

=14/86

disease causing

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over