rs572278771

chr19-15540490-G-Achr19-15540490-G-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM1 BP4_Strong BP6_Very_Strong BS1

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. 14/21 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
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts P:1 U:1 B:2
• Conservation: PhyloP100: 0.586

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 4 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 id 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 male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYP4F22	NM_173483.4	c.712G>A	p.Ala238Thr	missense_variant	8/14	ENST00000269703.8
CYP4F22	XM_011527692.3	c.712G>A	p.Ala238Thr	missense_variant	9/15
CYP4F22	XM_011527693.3	c.712G>A	p.Ala238Thr	missense_variant	8/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP4F22	ENST00000269703.8	c.712G>A	p.Ala238Thr	missense_variant	8/14	2	NM_173483.4	P1
CYP4F22	ENST00000601005.2	c.712G>A	p.Ala238Thr	missense_variant	6/12	5		P1

Frequencies

GnomAD3 genomes AF: 0.000184 AC: 28 AN: 152114 Hom.: 0 Cov.: 33

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

GnomAD3 exomes AF: 0.000780 AC: 196 AN: 251372 Hom.: 0 AF XY: 0.00107 AC XY: 145 AN XY: 135890

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 SAS exome AF: 0.00621

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.: 5 Cov.: 32 AF XY: 0.000562 AC XY: 409 AN XY: 727242

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00612

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.000513

GnomAD4 genome AF: 0.000184 AC: 28 AN: 152232 Hom.: 0 Cov.: 33 AF XY: 0.000242 AC XY: 18 AN XY: 74428

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00477

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000133 Hom.: 0

Bravo AF: 0.0000680

ExAC AF: 0.000873 AC: 106

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

Significance: Likely benign

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

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive congenital ichthyosis 5 Pathogenic:1 Uncertain:1

Pathogenic, no assertion criteria provided	clinical testing	Institute for Human Genetics, University Medical Center Freiburg	Apr 23, 2018	- -
Uncertain significance, no assertion criteria provided	clinical testing	Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	Jul 31, 2018	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Sep 03, 2022

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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 08, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.13
Cadd	Benign	16
Dann	Benign	0.97
DEOGEN2	Benign	0.049	T;T
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.62
FATHMM_MKL	Benign	0.093	N
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.018	T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.79	N;N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.46	T
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	T
GERP RS		4.3
Varity_R		0.10
gMVP		0.25

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

LitVar

Other links and lift over

dbSNP: rs572278771; hg19: chr19-15651301; COSMIC: COSV54112078;