19-15879621-C-T

Variant names:

• chr19-15879621-C-T
• rs2108622
• NM_001082.5:c.1297G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001082.5(CYP4F2):​c.1297G>A​(p.Val433Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.288 in 1,613,898 control chromosomes in the GnomAD database, including 69,909 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as drug response (★★★).

• Frequency:
  • Genomes: 𝑓 0.23 (4700 hom., cov: 31)
  • Exomes 𝑓: 0.29 (65209 hom.)
• Consequence: CYP4F2 NM_001082.5 missense
• Clinical Significance: drug response reviewed by expert panel B:2 O:2
• Conservation: PhyloP100: 1.68
• Publications: 550 publications found

Genes affected

CYP4F2 (HGNC:2645): (cytochrome P450 family 4 subfamily F member 2) 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 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, CYP4F11, is approximately 16 kb away. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009836018).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.386 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP4F2	NM_001082.5	c.1297G>A	p.Val433Met	missense_variant	Exon 11 of 13	ENST00000221700.11	NP_001073.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP4F2	ENST00000221700.11	c.1297G>A	p.Val433Met	missense_variant	Exon 11 of 13	1	NM_001082.5	ENSP00000221700.3

Frequencies

GnomAD3 genomes AF: 0.230 AC: 34923 AN: 151950 Hom.: 4697 Cov.: 31

Gnomad AFR AF: 0.0991

Gnomad AMI AF: 0.202

Gnomad AMR AF: 0.258

Gnomad ASJ AF: 0.347

Gnomad EAS AF: 0.245

Gnomad SAS AF: 0.402

Gnomad FIN AF: 0.199

Gnomad MID AF: 0.396

Gnomad NFE AF: 0.286

Gnomad OTH AF: 0.291

GnomAD2 exomes AF: 0.273 AC: 68663 AN: 251380 AF XY: 0.286

Gnomad AFR exome AF: 0.0966

Gnomad AMR exome AF: 0.229

Gnomad ASJ exome AF: 0.345

Gnomad EAS exome AF: 0.249

Gnomad FIN exome AF: 0.197

Gnomad NFE exome AF: 0.289

Gnomad OTH exome AF: 0.295

GnomAD4 exome AF: 0.294 AC: 429090 AN: 1461830 Hom.: 65209 Cov.: 41 AF XY: 0.298 AC XY: 216369 AN XY: 727224

African (AFR) AF: 0.0961 AC: 3218 AN: 33478

American (AMR) AF: 0.229 AC: 10224 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.348 AC: 9084 AN: 26136

East Asian (EAS) AF: 0.269 AC: 10694 AN: 39690

South Asian (SAS) AF: 0.390 AC: 33611 AN: 86252

European-Finnish (FIN) AF: 0.196 AC: 10447 AN: 53418

Middle Eastern (MID) AF: 0.380 AC: 2187 AN: 5762

European-Non Finnish (NFE) AF: 0.298 AC: 331882 AN: 1111982

Other (OTH) AF: 0.294 AC: 17743 AN: 60392

GnomAD4 genome AF: 0.230 AC: 34933 AN: 152068 Hom.: 4700 Cov.: 31 AF XY: 0.230 AC XY: 17063 AN XY: 74330

African (AFR) AF: 0.0990 AC: 4110 AN: 41506

American (AMR) AF: 0.258 AC: 3942 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.347 AC: 1204 AN: 3468

East Asian (EAS) AF: 0.246 AC: 1269 AN: 5158

South Asian (SAS) AF: 0.401 AC: 1929 AN: 4810

European-Finnish (FIN) AF: 0.199 AC: 2102 AN: 10566

Middle Eastern (MID) AF: 0.391 AC: 115 AN: 294

European-Non Finnish (NFE) AF: 0.286 AC: 19457 AN: 67966

Other (OTH) AF: 0.294 AC: 621 AN: 2110

Alfa AF: 0.272 Hom.: 21849

Bravo AF: 0.226

TwinsUK AF: 0.308 AC: 1143

ALSPAC AF: 0.301 AC: 1160

ESP6500AA AF: 0.0971 AC: 428

ESP6500EA AF: 0.291 AC: 2504

ExAC AF: 0.272 AC: 33078

Asia WGS AF: 0.332 AC: 1154 AN: 3478

EpiCase AF: 0.300

EpiControl AF: 0.309

ClinVar

Significance: drug response

Submissions summary: Benign:2 Other:2

Revision: reviewed by expert panel

Submissions by phenotype

CYP4F2-related disorder Benign:1

Jul 22, 2021

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

May 12, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

warfarin response - Dosage Other:1

Mar 24, 2021

PharmGKB

Significance: drug response

Review Status: reviewed by expert panel

Collection Method: curation

PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or an FDA-approved drug label annotation. Annotations of drug labels or clinical guidelines must give prescribing guidance for specific variants (e.g. CYP2C9*3, HLA-B*57:01) or provide mapping from defined allele functions to diplotypes and phenotypes to be used as supporting evidence for a level 1A clinical annotation. Level 1A clinical annotations must also be supported by at least one publication in addition to a clinical guideline or drug label with variant-specific prescribing guidance. Drug-variant association: Dosage

acenocoumarol response - Dosage Other:1

Mar 24, 2021

PharmGKB

Significance: drug response

Review Status: reviewed by expert panel

Collection Method: curation

PharmGKB Level of Evidence 2A: Variants in Level 2A clinical annotations are found in PharmGKB’s Tier 1 Very Important Pharmacogenes (VIPs). These variants are in known pharmacogenes, implying causation of drug phenotype is more likely. These clinical annotations describe variant-drug combinations with a moderate level of evidence supporting the association. For example, the association may be found in multiple cohorts, but there may be a minority of studies that do not support the majority assertion. Level 2A clinical annotations must be supported by at least two independent publications. Drug-variant association: Dosage

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.31
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.14	T;.
Eigen	Uncertain	0.33
Eigen_PC	Benign	0.13
FATHMM_MKL	Benign	0.57	D
LIST_S2	Benign	0.80	T;T
MetaRNN	Benign	0.0098	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Pathogenic	4.0	H;.
PhyloP100		1.7
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-2.7	D;.
REVEL	Uncertain	0.30
Sift	Uncertain	0.0050	D;.
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;.
Vest4		0.14
MPC		0.64
ClinPred		0.050	T
GERP RS		1.7
Varity_R		0.65
gMVP		0.81
Mutation Taster		=92/8	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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

Other links and lift over

dbSNP: rs2108622; hg19: chr19-15990431; COSMIC: COSV55616921; COSMIC: COSV55616921;