Genetic Variant CYP4F3:p.Arg365Cys (chr19-15652930-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_000896.3(CYP4F3):c.1093C>T(p.Arg365Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000686 in 1,458,718 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000069 ( 0 hom. )

Consequence

CYP4F3
NM_000896.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.936

Publications

1 publications found

Variant links:

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]

CYP4F3 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP4F3	NM_000896.3 link	c.1093C>T	p.Arg365Cys	missense_variant	Exon 9 of 13	ENST00000221307.13	NP_000887.2	Q08477-1A0A024R7J8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP4F3	ENST00000221307.13 link	c.1093C>T	p.Arg365Cys	missense_variant	Exon 9 of 13	1	NM_000896.3	ENSP00000221307.6		Q08477-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000403

AC:

AN:

247962

AF XY:

0.00000746

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000892

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000686

AC:

AN:

1458718

Hom.:

Cov.:

AF XY:

0.00000827

AC XY:

AN XY:

725618

show subpopulations

African (AFR)

AF:

0.0000599

AC:

AN:

33390

American (AMR)

AF:

0.0000225

AC:

AN:

44370

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25856

East Asian (EAS)

AF:

0.00

AC:

AN:

39678

South Asian (SAS)

AF:

0.0000116

AC:

AN:

85904

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53142

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5744

European-Non Finnish (NFE)

AF:

0.00000540

AC:

AN:

1110352

Other (OTH)

AF:

0.00

AC:

AN:

60282

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 08, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1093C>T (p.R365C) alteration is located in exon 9 (coding exon 8) of the CYP4F3 gene. This alteration results from a C to T substitution at nucleotide position 1093, causing the arginine (R) at amino acid position 365 to be replaced by a cysteine (C). 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

0.12

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Uncertain

-0.070

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.077

.;.;T;.

Eigen

Benign

0.059

Eigen_PC

Benign

0.055

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.82

.;.;T;T

M_CAP

Benign

0.039

MetaRNN

Uncertain

0.73

D;D;D;D

MetaSVM

Benign

-0.43

MutationAssessor

Pathogenic

3.3

M;M;M;M

PhyloP100

0.94

PrimateAI

Benign

0.35

PROVEAN

Pathogenic

-7.0

.;.;D;.

REVEL

Uncertain

0.42

Sift

Uncertain

0.0060

.;.;D;.

Sift4G

Uncertain

0.028

D;D;D;D

Polyphen

0.45

.;.;B;.

Vest4

0.57

MutPred

0.59

Loss of solvent accessibility (P = 0.0036);Loss of solvent accessibility (P = 0.0036);Loss of solvent accessibility (P = 0.0036);Loss of solvent accessibility (P = 0.0036);

MVP

0.60

MPC

0.12

ClinPred

0.69

GERP RS

2.9

Varity_R

0.42

gMVP

0.53

Mutation Taster

=70/30

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over