19-15658720-C-T

Variant names:

• chr19-15658720-C-T
• rs4646519
• NM_000896.3:c.1315-7C>T

Variant summary

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

The NM_000896.3(CYP4F3):​c.1315-7C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.39 in 1,613,178 control chromosomes in the GnomAD database, including 128,597 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.46 (17351 hom., cov: 30)
  • Exomes 𝑓: 0.38 (111246 hom.)
• Consequence: CYP4F3 NM_000896.3 splice_region, intron
• Scores: Splicing: ADA: 0.0001283
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.72
• Publications: 9 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.635 is higher than 0.05.

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.1315-7C>T		splice_region intron	N/A	NP_000887.2	Q08477-1
	CYP4F3	NM_001199208.2		c.1315-7C>T		splice_region intron	N/A	NP_001186137.1	Q08477-2
	CYP4F3	NM_001199209.2		c.1315-7C>T		splice_region intron	N/A	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.1315-7C>T		splice_region intron	N/A	ENSP00000221307.6	Q08477-1
	CYP4F3	ENST00000585846.1	TSL:1	c.1315-7C>T		splice_region intron	N/A	ENSP00000468105.1	Q08477-2
	CYP4F3	ENST00000591058.5	TSL:1	c.1315-7C>T		splice_region intron	N/A	ENSP00000466988.1	Q08477-2

Frequencies

GnomAD3 genomes AF: 0.461 AC: 69944 AN: 151600 Hom.: 17338 Cov.: 30

Gnomad AFR AF: 0.622

Gnomad AMI AF: 0.411

Gnomad AMR AF: 0.513

Gnomad ASJ AF: 0.369

Gnomad EAS AF: 0.654

Gnomad SAS AF: 0.374

Gnomad FIN AF: 0.399

Gnomad MID AF: 0.452

Gnomad NFE AF: 0.360

Gnomad OTH AF: 0.429

GnomAD2 exomes AF: 0.435 AC: 109270 AN: 250970 AF XY: 0.420

Gnomad AFR exome AF: 0.628

Gnomad AMR exome AF: 0.573

Gnomad ASJ exome AF: 0.369

Gnomad EAS exome AF: 0.658

Gnomad FIN exome AF: 0.402

Gnomad NFE exome AF: 0.360

Gnomad OTH exome AF: 0.406

GnomAD4 exome AF: 0.382 AC: 558688 AN: 1461460 Hom.: 111246 Cov.: 47 AF XY: 0.380 AC XY: 276468 AN XY: 727034

African (AFR) AF: 0.630 AC: 21076 AN: 33462

American (AMR) AF: 0.565 AC: 25243 AN: 44676

Ashkenazi Jewish (ASJ) AF: 0.368 AC: 9615 AN: 26120

East Asian (EAS) AF: 0.655 AC: 25997 AN: 39688

South Asian (SAS) AF: 0.376 AC: 32456 AN: 86238

European-Finnish (FIN) AF: 0.401 AC: 21439 AN: 53414

Middle Eastern (MID) AF: 0.401 AC: 2311 AN: 5766

European-Non Finnish (NFE) AF: 0.357 AC: 396449 AN: 1111720

Other (OTH) AF: 0.399 AC: 24102 AN: 60376

GnomAD4 genome AF: 0.461 AC: 70010 AN: 151718 Hom.: 17351 Cov.: 30 AF XY: 0.465 AC XY: 34441 AN XY: 74116

African (AFR) AF: 0.622 AC: 25713 AN: 41350

American (AMR) AF: 0.513 AC: 7829 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.369 AC: 1278 AN: 3468

East Asian (EAS) AF: 0.654 AC: 3340 AN: 5110

South Asian (SAS) AF: 0.373 AC: 1795 AN: 4806

European-Finnish (FIN) AF: 0.399 AC: 4200 AN: 10534

Middle Eastern (MID) AF: 0.452 AC: 132 AN: 292

European-Non Finnish (NFE) AF: 0.360 AC: 24443 AN: 67872

Other (OTH) AF: 0.431 AC: 907 AN: 2106

Alfa AF: 0.393 Hom.: 5285

Bravo AF: 0.478

Asia WGS AF: 0.525 AC: 1823 AN: 3478

EpiCase AF: 0.364

EpiControl AF: 0.366

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	1.2
DANN	Benign	0.34
PhyloP100		-2.7
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00013
dbscSNV1_RF	Benign	0.0060
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: rs4646519; hg19: chr19-15769530; COSMIC: COSV105019623; COSMIC: COSV105019623;