19-15641579-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_000896.3(CYP4F3):c.164C>G(p.Pro55Arg) 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 pathogenic 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 (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: CYP4F3 NM_000896.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.59

Genes affected

CYP4F3 (HGNC:2646): (cytochrome P450 family 4 subfamily F member 3) This gene, CYP4F3, 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 protein localizes to the endoplasmic reticulum. The enzyme starts the process of inactivating and degrading leukotriene B4, a potent mediator of inflammation. This gene is part of a cluster of cytochrome P450 genes on chromosome 19. Another member of this family, CYP4F8, is approximately 18 kb away. Several transcript variants encoding two different isoforms have been found for this gene. [provided by RefSeq, Apr 2019]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.776

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYP4F3	NM_000896.3	c.164C>G	p.Pro55Arg	missense_variant	2/13	ENST00000221307.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP4F3	ENST00000221307.13	c.164C>G	p.Pro55Arg	missense_variant	2/13	1	NM_000896.3	A1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 07, 2023

The c.164C>G (p.P55R) alteration is located in exon 2 (coding exon 1) of the CYP4F3 gene. This alteration results from a C to G substitution at nucleotide position 164, causing the proline (P) at amino acid position 55 to be replaced by an arginine (R). 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	0.11
BayesDel_addAF	Benign	-0.074	T
BayesDel_noAF	Benign	-0.34
Cadd	Benign	15
Dann	Uncertain	0.99
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.14	N
M_CAP	Benign	0.035	D
MetaRNN	Pathogenic	0.78	D;D;D;D
MetaSVM	Benign	-0.36	T
MutationAssessor	Uncertain	2.3	M;M;M;M
MutationTaster	Benign	0.96	N;N;N;N
PrimateAI	Benign	0.38	T
Sift4G	Uncertain	0.018	D;D;D;D
Polyphen		0.28	.;.;B;.
Vest4		0.46
MutPred		0.82		Loss of glycosylation at P55 (P = 0.0054);Loss of glycosylation at P55 (P = 0.0054);Loss of glycosylation at P55 (P = 0.0054);Loss of glycosylation at P55 (P = 0.0054);
MVP		0.55
MPC		0.13
ClinPred		0.78	D
GERP RS		2.9
Varity_R		0.26
gMVP		0.72

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-15752389;