19-15525458-G-C

Variant names:

• chr19-15525458-G-C
• rs142720535
• NM_173483.4:c.122G>C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_173483.4(CYP4F22):​c.122G>C​(p.Arg41Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. R41R) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CYP4F22 NM_173483.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.888

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.33486554).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP4F22	NM_173483.4	c.122G>C	p.Arg41Pro	missense_variant	Exon 3 of 14	ENST00000269703.8	NP_775754.2
CYP4F22	XM_011527692.3	c.122G>C	p.Arg41Pro	missense_variant	Exon 4 of 15		XP_011525994.1
CYP4F22	XM_011527693.3	c.122G>C	p.Arg41Pro	missense_variant	Exon 3 of 14		XP_011525995.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP4F22	ENST00000269703.8	c.122G>C	p.Arg41Pro	missense_variant	Exon 3 of 14	2	NM_173483.4	ENSP00000269703.1
CYP4F22	ENST00000601005.2	c.122G>C	p.Arg41Pro	missense_variant	Exon 1 of 12	5		ENSP00000469866.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Feb 03, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.122G>C (p.R41P) alteration is located in exon 3 (coding exon 1) of the CYP4F22 gene. This alteration results from a G to C substitution at nucleotide position 122, causing the arginine (R) at amino acid position 41 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Uncertain	0.017	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	2.4
DANN	Benign	0.80
DEOGEN2	Benign	0.29	T;T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.025	N
LIST_S2	Benign	0.35	.;T
M_CAP	Benign	0.051	D
MetaRNN	Benign	0.33	T;T
MetaSVM	Benign	-0.65	T
MutationAssessor	Uncertain	2.2	M;M
PrimateAI	Benign	0.26	T
PROVEAN	Uncertain	-3.4	D;.
REVEL	Uncertain	0.35
Sift	Uncertain	0.0080	D;.
Sift4G	Benign	0.066	T;T
Polyphen		0.033	B;B
Vest4		0.34
MutPred		0.66		Loss of MoRF binding (P = 8e-04);Loss of MoRF binding (P = 8e-04);
MVP		0.23
MPC		0.34
ClinPred		0.31	T
GERP RS		-8.3
Varity_R		0.43
gMVP		0.85

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: rs142720535; hg19: chr19-15636269;