rs11666601

chr19-15537904-G-Achr19-15537904-G-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_173483.4(CYP4F22):c.582G>A(p.Ala194=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.109 in 1,613,962 control chromosomes in the GnomAD database, including 10,055 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.093 (744 hom., cov: 31)
  • Exomes 𝑓: 0.11 (9311 hom.)
• Consequence: CYP4F22 NM_173483.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.167

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BP6: Variant 19-15537904-G-A is Benign according to our data. Variant chr19-15537904-G-A is described in ClinVar as [Benign]. Clinvar id is 262835.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-15537904-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.167 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.114 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYP4F22	NM_173483.4	c.582G>A	p.Ala194=	synonymous_variant	7/14	ENST00000269703.8
CYP4F22	XM_011527692.3	c.582G>A	p.Ala194=	synonymous_variant	8/15
CYP4F22	XM_011527693.3	c.582G>A	p.Ala194=	synonymous_variant	7/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP4F22	ENST00000269703.8	c.582G>A	p.Ala194=	synonymous_variant	7/14	2	NM_173483.4	P1
CYP4F22	ENST00000601005.2	c.582G>A	p.Ala194=	synonymous_variant	5/12	5		P1

Frequencies

GnomAD3 genomes AF: 0.0930 AC: 14137 AN: 152054 Hom.: 742 Cov.: 31

Gnomad AFR AF: 0.0563

Gnomad AMI AF: 0.0987

Gnomad AMR AF: 0.0798

Gnomad ASJ AF: 0.131

Gnomad EAS AF: 0.0693

Gnomad SAS AF: 0.0923

Gnomad FIN AF: 0.102

Gnomad MID AF: 0.133

Gnomad NFE AF: 0.116

Gnomad OTH AF: 0.102

GnomAD3 exomes AF: 0.0960 AC: 24148 AN: 251458 Hom.: 1246 AF XY: 0.0991 AC XY: 13469 AN XY: 135894

Gnomad AFR exome AF: 0.0536

Gnomad AMR exome AF: 0.0558

Gnomad ASJ exome AF: 0.133

Gnomad EAS exome AF: 0.0787

Gnomad SAS exome AF: 0.0951

Gnomad FIN exome AF: 0.104

Gnomad NFE exome AF: 0.112

Gnomad OTH exome AF: 0.102

GnomAD4 exome AF: 0.111 AC: 161862 AN: 1461790 Hom.: 9311 Cov.: 35 AF XY: 0.110 AC XY: 80312 AN XY: 727190

Gnomad4 AFR exome AF: 0.0557

Gnomad4 AMR exome AF: 0.0585

Gnomad4 ASJ exome AF: 0.135

Gnomad4 EAS exome AF: 0.0513

Gnomad4 SAS exome AF: 0.0942

Gnomad4 FIN exome AF: 0.103

Gnomad4 NFE exome AF: 0.118

Gnomad4 OTH exome AF: 0.112

GnomAD4 genome AF: 0.0930 AC: 14156 AN: 152172 Hom.: 744 Cov.: 31 AF XY: 0.0921 AC XY: 6851 AN XY: 74380

Gnomad4 AFR AF: 0.0564

Gnomad4 AMR AF: 0.0797

Gnomad4 ASJ AF: 0.131

Gnomad4 EAS AF: 0.0695

Gnomad4 SAS AF: 0.0934

Gnomad4 FIN AF: 0.102

Gnomad4 NFE AF: 0.116

Gnomad4 OTH AF: 0.100

Alfa AF: 0.110 Hom.: 1563

Bravo AF: 0.0889

Asia WGS AF: 0.0770 AC: 269 AN: 3478

EpiCase AF: 0.118

EpiControl AF: 0.119

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Autosomal recessive congenital ichthyosis 5 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
Cadd	Benign	9.7
Dann	Benign	0.49

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

LitVar

Other links and lift over

dbSNP: rs11666601; hg19: chr19-15648715; COSMIC: COSV54112318;