Genetic Variant CYP4F22:p.Gly81Val (chr19-15529728-G-T) – ACMG Classification: Uncertain_significance (5 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2PM5PP3

The NM_173483.4(CYP4F22):c.242G>T(p.Gly81Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. G81D) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

CYP4F22
NM_173483.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.45

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:

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ACMG classification

Classification was made for transcript

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

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr19-15529728-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 560306.Status of the report is criteria_provided_single_submitter, 1 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.81

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.242G>T	p.Gly81Val	missense	Exon 4 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.242G>T	p.Gly81Val	missense	Exon 4 of 14	ENSP00000269703.1
	CYP4F22	ENST00000601005.2	TSL:5	c.242G>T	p.Gly81Val	missense	Exon 2 of 12	ENSP00000469866.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00000824

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.58

BayesDel_addAF

Pathogenic

0.33

BayesDel_noAF

Pathogenic

0.23

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.30

Eigen

Uncertain

0.24

Eigen_PC

Uncertain

0.27

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.78

M_CAP

Benign

0.075

MetaRNN

Pathogenic

0.81

MetaSVM

Pathogenic

0.83

MutationAssessor

Benign

1.9

PhyloP100

5.4

PrimateAI

Uncertain

0.50

PROVEAN

Pathogenic

-6.9

REVEL

Pathogenic

0.72

Sift

Benign

0.067

Sift4G

Uncertain

0.032

Polyphen

0.90

Vest4

0.55

MVP

0.94

MPC

0.84

ClinPred

0.93

GERP RS

5.4

Varity_R

0.82

gMVP

0.77

Mutation Taster

=18/82

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over