rs28371536

Variant names:

• chr19-15650073-G-A
• rs28371536
• NM_000896.3:c.808G>A

Variant summary

Our verdict is Benign. The variant received -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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• 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
• Publications: 4 publications found

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

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 777722.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000896.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP4F3	NM_000896.3	MANE Select	c.808G>A	p.Val270Ile	missense	Exon 7 of 13	NP_000887.2	Q08477-1
	CYP4F3	NM_001199208.2		c.808G>A	p.Val270Ile	missense	Exon 7 of 13	NP_001186137.1	Q08477-2
	CYP4F3	NM_001199209.2		c.808G>A	p.Val270Ile	missense	Exon 7 of 13	NP_001186138.1	Q08477-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP4F3	ENST00000221307.13	TSL:1 MANE Select	c.808G>A	p.Val270Ile	missense	Exon 7 of 13	ENSP00000221307.6	Q08477-1
	CYP4F3	ENST00000585846.1	TSL:1	c.808G>A	p.Val270Ile	missense	Exon 6 of 12	ENSP00000468105.1	Q08477-2
	CYP4F3	ENST00000591058.5	TSL:1	c.808G>A	p.Val270Ile	missense	Exon 7 of 13	ENSP00000466988.1	Q08477-2

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

GnomAD2 exomes AF: 0.00634 AC: 1594 AN: 251492 AF XY: 0.00642

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 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

African (AFR) AF: 0.00114 AC: 38 AN: 33480

American (AMR) AF: 0.00443 AC: 198 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000957 AC: 25 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00232 AC: 200 AN: 86258

European-Finnish (FIN) AF: 0.0117 AC: 626 AN: 53420

Middle Eastern (MID) AF: 0.000867 AC: 5 AN: 5768

European-Non Finnish (NFE) AF: 0.00948 AC: 10545 AN: 1111998

Other (OTH) AF: 0.00762 AC: 460 AN: 60396

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

African (AFR) AF: 0.00128 AC: 53 AN: 41552

American (AMR) AF: 0.00268 AC: 41 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00187 AC: 9 AN: 4824

European-Finnish (FIN) AF: 0.00933 AC: 99 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0102 AC: 696 AN: 68014

Other (OTH) AF: 0.00614 AC: 13 AN: 2116

Alfa AF: 0.00873 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

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

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
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	1.7	L
PhyloP100		4.1
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.88	N
REVEL	Benign	0.047
Sift	Benign	0.051	T
Sift4G	Benign	0.14	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
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs28371536; hg19: chr19-15760883; COSMIC: COSV106369914; COSMIC: COSV106369914;