rs28371536

Positions:

• chr19-15650073-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_000896.3(CYP4F3):​c.808G>A​(p.Val270Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00806 in 1,614,152 control chromosomes in the GnomAD database, including 60 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0060 (3 hom., cov: 31)
  • Exomes 𝑓: 0.0083 (57 hom.)
• Consequence: CYP4F3 NM_000896.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 4.11

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 Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011344999).
• BP6: Variant 19-15650073-G-A is Benign according to our data. Variant chr19-15650073-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 777722.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-15650073-G-A is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYP4F3	NM_000896.3	c.808G>A	p.Val270Ile	missense_variant	7/13	ENST00000221307.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP4F3	ENST00000221307.13	c.808G>A	p.Val270Ile	missense_variant	7/13	1	NM_000896.3	A1

Frequencies

GnomAD3 genomes AF: 0.00605 AC: 920 AN: 152154 Hom.: 3 Cov.: 31

Gnomad AFR AF: 0.00128

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.00269

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.00933

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0102

Gnomad OTH AF: 0.00621

GnomAD3 exomes AF: 0.00634 AC: 1594 AN: 251492 Hom.: 10 AF XY: 0.00642 AC XY: 873 AN XY: 135920

Gnomad AFR exome AF: 0.000615

Gnomad AMR exome AF: 0.00416

Gnomad ASJ exome AF: 0.000893

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00242

Gnomad FIN exome AF: 0.00975

Gnomad NFE exome AF: 0.00968

Gnomad OTH exome AF: 0.00733

GnomAD4 exome AF: 0.00827 AC: 12097 AN: 1461880 Hom.: 57 Cov.: 32 AF XY: 0.00823 AC XY: 5987 AN XY: 727244

Gnomad4 AFR exome AF: 0.00114

Gnomad4 AMR exome AF: 0.00443

Gnomad4 ASJ exome AF: 0.000957

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00232

Gnomad4 FIN exome AF: 0.0117

Gnomad4 NFE exome AF: 0.00948

Gnomad4 OTH exome AF: 0.00762

GnomAD4 genome AF: 0.00604 AC: 919 AN: 152272 Hom.: 3 Cov.: 31 AF XY: 0.00598 AC XY: 445 AN XY: 74436

Gnomad4 AFR AF: 0.00128

Gnomad4 AMR AF: 0.00268

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00187

Gnomad4 FIN AF: 0.00933

Gnomad4 NFE AF: 0.0102

Gnomad4 OTH AF: 0.00614

Alfa AF: 0.00916 Hom.: 4

Bravo AF: 0.00529

TwinsUK AF: 0.00647 AC: 24

ALSPAC AF: 0.00882 AC: 34

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00930 AC: 80

ExAC AF: 0.00628 AC: 763

EpiCase AF: 0.00823

EpiControl AF: 0.00800

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

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	Feb 01, 2023	CYP4F3: BP4, BS2 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 02, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0045	.;.;T;.
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.35
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.83	.;.;T;T
MetaRNN	Benign	0.011	T;T;T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	1.7	L;L;L;L
MutationTaster	Benign	0.97	D;D;D;D
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.88	.;.;N;.
REVEL	Benign	0.047
Sift	Benign	0.051	.;.;T;.
Sift4G	Benign	0.14	T;T;T;T
Polyphen		0.050	.;.;B;.
Vest4		0.29
MVP		0.49
MPC		0.056
ClinPred		0.028	T
GERP RS		2.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.098
gMVP		0.13

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: rs28371536; hg19: chr19-15760883;