19-15525513-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_173483.4(CYP4F22):c.177C>T(p.Phe59=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0102 in 1,612,182 control chromosomes in the GnomAD database, including 109 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0083 (10 hom., cov: 32)
  • Exomes 𝑓: 0.010 (99 hom.)
• Consequence: CYP4F22 NM_173483.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.06

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.3).
• BP6: Variant 19-15525513-C-T is Benign according to our data. Variant chr19-15525513-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 719452.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-15525513-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=2.06 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00831 (1265/152310) while in subpopulation NFE AF= 0.012 (813/68012). AF 95% confidence interval is 0.0113. There are 10 homozygotes in gnomad4. There are 652 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYP4F22	NM_173483.4	c.177C>T	p.Phe59=	synonymous_variant	3/14	ENST00000269703.8
CYP4F22	XM_011527692.3	c.177C>T	p.Phe59=	synonymous_variant	4/15
CYP4F22	XM_011527693.3	c.177C>T	p.Phe59=	synonymous_variant	3/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP4F22	ENST00000269703.8	c.177C>T	p.Phe59=	synonymous_variant	3/14	2	NM_173483.4	P1
CYP4F22	ENST00000601005.2	c.177C>T	p.Phe59=	synonymous_variant	1/12	5		P1

Frequencies

GnomAD3 genomes AF: 0.00833 AC: 1267 AN: 152192 Hom.: 10 Cov.: 32

Gnomad AFR AF: 0.00200

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00682

Gnomad FIN AF: 0.0271

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0120

Gnomad OTH AF: 0.00430

GnomAD3 exomes AF: 0.00840 AC: 2097 AN: 249736 Hom.: 14 AF XY: 0.00858 AC XY: 1159 AN XY: 135138

Gnomad AFR exome AF: 0.00136

Gnomad AMR exome AF: 0.00153

Gnomad ASJ exome AF: 0.0000994

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00581

Gnomad FIN exome AF: 0.0271

Gnomad NFE exome AF: 0.0110

Gnomad OTH exome AF: 0.00736

GnomAD4 exome AF: 0.0104 AC: 15168 AN: 1459872 Hom.: 99 Cov.: 32 AF XY: 0.0103 AC XY: 7472 AN XY: 726332

Gnomad4 AFR exome AF: 0.00117

Gnomad4 AMR exome AF: 0.00206

Gnomad4 ASJ exome AF: 0.000153

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00554

Gnomad4 FIN exome AF: 0.0269

Gnomad4 NFE exome AF: 0.0113

Gnomad4 OTH exome AF: 0.00873

GnomAD4 genome AF: 0.00831 AC: 1265 AN: 152310 Hom.: 10 Cov.: 32 AF XY: 0.00875 AC XY: 652 AN XY: 74482

Gnomad4 AFR AF: 0.00197

Gnomad4 AMR AF: 0.00262

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00683

Gnomad4 FIN AF: 0.0271

Gnomad4 NFE AF: 0.0120

Gnomad4 OTH AF: 0.00425

Alfa AF: 0.00866 Hom.: 5

Bravo AF: 0.00601

Asia WGS AF: 0.00462 AC: 16 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2023	CYP4F22: BP4, BP7 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 13, 2023	- -

Autosomal recessive congenital ichthyosis 5 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.30
Cadd	Benign	6.9
Dann	Benign	0.83

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: rs118091316; hg19: chr19-15636324;