19-15649205-A-G

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_000896.3(CYP4F3):c.571A>G(p.Met191Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00629 in 1,613,464 control chromosomes in the GnomAD database, including 46 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0039 (1 hom., cov: 31)
  • Exomes 𝑓: 0.0065 (45 hom.)
• Consequence: CYP4F3 NM_000896.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.20

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009785503).
• BP6: Variant 19-15649205-A-G is Benign according to our data. Variant chr19-15649205-A-G is described in ClinVar as [Benign]. Clinvar id is 777900.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAdExome at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYP4F3	NM_000896.3	c.571A>G	p.Met191Val	missense_variant	6/13	ENST00000221307.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP4F3	ENST00000221307.13	c.571A>G	p.Met191Val	missense_variant	6/13	1	NM_000896.3	A1

Frequencies

GnomAD3 genomes AF: 0.00391 AC: 595 AN: 152150 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.00133

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00281

Gnomad ASJ AF: 0.0147

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00635

Gnomad OTH AF: 0.00621

GnomAD3 exomes AF: 0.00428 AC: 1077 AN: 251490 Hom.: 8 AF XY: 0.00416 AC XY: 566 AN XY: 135922

Gnomad AFR exome AF: 0.00117

Gnomad AMR exome AF: 0.00387

Gnomad ASJ exome AF: 0.0165

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.000231

Gnomad NFE exome AF: 0.00638

Gnomad OTH exome AF: 0.00423

GnomAD4 exome AF: 0.00654 AC: 9550 AN: 1461196 Hom.: 45 Cov.: 30 AF XY: 0.00630 AC XY: 4580 AN XY: 726904

Gnomad4 AFR exome AF: 0.00105

Gnomad4 AMR exome AF: 0.00390

Gnomad4 ASJ exome AF: 0.0155

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.000356

Gnomad4 NFE exome AF: 0.00768

Gnomad4 OTH exome AF: 0.00621

GnomAD4 genome AF: 0.00390 AC: 594 AN: 152268 Hom.: 1 Cov.: 31 AF XY: 0.00341 AC XY: 254 AN XY: 74450

Gnomad4 AFR AF: 0.00132

Gnomad4 AMR AF: 0.00281

Gnomad4 ASJ AF: 0.0147

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.00634

Gnomad4 OTH AF: 0.00615

Alfa AF: 0.00674 Hom.: 6

Bravo AF: 0.00476

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00686 AC: 59

ExAC AF: 0.00393 AC: 477

EpiCase AF: 0.00742

EpiControl AF: 0.00682

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jul 21, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.41
Cadd	Benign	19
Dann	Benign	0.94
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.21
FATHMM_MKL	Benign	0.67	D
MetaRNN	Benign	0.0098	T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.2	L;L;L;L
MutationTaster	Benign	0.97	N;N;N;N
PrimateAI	Benign	0.42	T
Sift4G	Benign	0.22	T;T;T;T
Polyphen		0.0040	.;.;B;.
Vest4		0.20
MVP		0.53
MPC		0.039
ClinPred		0.0067	T
GERP RS		2.3
Varity_R		0.23
gMVP		0.37

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: rs61734307; hg19: chr19-15760015;