19-15525404-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 2P and 10B. PM2 BP4_Strong BP6_Moderate BS1

The NM_173483.4(CYP4F22):c.68C>T(p.Ala23Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000103 in 1,614,196 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00034 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000078 (0 hom.)
• Consequence: CYP4F22 NM_173483.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.920

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 -8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.024261922).
• BP6: Variant 19-15525404-C-T is Benign according to our data. Variant chr19-15525404-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 1146419.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000341 (52/152354) while in subpopulation AFR AF= 0.0012 (50/41590). AF 95% confidence interval is 0.000937. There are 0 homozygotes in gnomad4. There are 26 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYP4F22	NM_173483.4	c.68C>T	p.Ala23Val	missense_variant	3/14	ENST00000269703.8
CYP4F22	XM_011527692.3	c.68C>T	p.Ala23Val	missense_variant	4/15
CYP4F22	XM_011527693.3	c.68C>T	p.Ala23Val	missense_variant	3/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP4F22	ENST00000269703.8	c.68C>T	p.Ala23Val	missense_variant	3/14	2	NM_173483.4	P1
CYP4F22	ENST00000601005.2	c.68C>T	p.Ala23Val	missense_variant	1/12	5		P1

Frequencies

GnomAD3 genomes AF: 0.000342 AC: 52 AN: 152236 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000135 AC: 34 AN: 251400 Hom.: 0 AF XY: 0.000125 AC XY: 17 AN XY: 135878

Gnomad AFR exome AF: 0.00111

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000704

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000780 AC: 114 AN: 1461842 Hom.: 0 Cov.: 32 AF XY: 0.0000784 AC XY: 57 AN XY: 727234

Gnomad4 AFR exome AF: 0.00146

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000139

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000369

Gnomad4 OTH exome AF: 0.0000828

GnomAD4 genome AF: 0.000341 AC: 52 AN: 152354 Hom.: 0 Cov.: 32 AF XY: 0.000349 AC XY: 26 AN XY: 74492

Gnomad4 AFR AF: 0.00120

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000970 Hom.: 0

Bravo AF: 0.000393

ESP6500AA AF: 0.00204 AC: 9

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000206 AC: 25

EpiCase AF: 0.0000545

EpiControl AF: 0.000178

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 07, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.31
Cadd	Benign	13
Dann	Uncertain	0.99
DEOGEN2	Benign	0.061	T;T
Eigen	Benign	-0.91
Eigen_PC	Benign	-0.86
FATHMM_MKL	Benign	0.086	N
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.024	T;T
MetaSVM	Benign	-0.56	T
MutationAssessor	Benign	1.8	L;L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.88	N;.
REVEL	Benign	0.24
Sift	Benign	0.28	T;.
Sift4G	Benign	0.16	T;T
Polyphen		0.0040	B;B
Vest4		0.26
MVP		0.62
MPC		0.22
ClinPred		0.026	T
GERP RS		3.6
Varity_R		0.037
gMVP		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: rs148402706; hg19: chr19-15636215;