Genetic Variant CYP4F8:p.Arg49Gln (chr19-15615762-G-A) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_007253.4(CYP4F8):c.146G>A(p.Arg49Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0058 in 1,613,938 control chromosomes in the GnomAD database, including 46 homozygotes. In-silico tool predicts a benign outcome for this variant. 10/13 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0053 ( 11 hom., cov: 31)

Exomes 𝑓: 0.0059 ( 35 hom. )

Consequence

CYP4F8
NM_007253.4 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.801

Variant links:

Genes affected

CYP4F8 (HGNC:2648): (cytochrome P450 family 4 subfamily F member 8) This gene, CYP4F8, 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 and functions as a 19-hydroxylase of prostaglandins in seminal vesicles. This gene is part of a cluster of cytochrome P450 genes on chromosome 19. Another member of this family, CYP4F3, is approximately 18 kb away. [provided by RefSeq, Jul 2008]

CYP4F8 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0040444434).

BP6

Variant 19-15615762-G-A is Benign according to our data. Variant chr19-15615762-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 2649496.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Homozygotes in GnomAd4 at 11 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP4F8	NM_007253.4 link	c.146G>A	p.Arg49Gln	missense_variant	Exon 2 of 13	ENST00000612078.5	NP_009184.1	P98187
CYP4F8	XM_024451341.2 link	c.146G>A	p.Arg49Gln	missense_variant	Exon 2 of 11		XP_024307109.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP4F8	ENST00000612078.5 link	c.146G>A	p.Arg49Gln	missense_variant	Exon 2 of 13	1	NM_007253.4	ENSP00000477567.1		P98187

Frequencies

GnomAD3 genomes

AF:

0.00530

AC:

806

AN:

152114

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00118

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00707

Gnomad ASJ

AF:

0.0355

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.00235

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.00687

Gnomad OTH

AF:

0.00912

GnomAD3 exomes

AF:

0.00564

AC:

1410

AN:

249968

Hom.:

AF XY:

0.00579

AC XY:

784

AN XY:

135478

show subpopulations

Gnomad AFR exome

AF:

0.00128

Gnomad AMR exome

AF:

0.00533

Gnomad ASJ exome

AF:

0.0305

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00131

Gnomad FIN exome

AF:

0.00185

Gnomad NFE exome

AF:

0.00672

Gnomad OTH exome

AF:

0.00971

GnomAD4 exome

AF:

0.00585

AC:

8554

AN:

1461706

Hom.:

Cov.:

AF XY:

0.00592

AC XY:

4303

AN XY:

727140

show subpopulations

Gnomad4 AFR exome

AF:

0.00120

Gnomad4 AMR exome

AF:

0.00550

Gnomad4 ASJ exome

AF:

0.0320

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00139

Gnomad4 FIN exome

AF:

0.00193

Gnomad4 NFE exome

AF:

0.00600

Gnomad4 OTH exome

AF:

0.00735

GnomAD4 genome

AF:

0.00528

AC:

804

AN:

152232

Hom.:

Cov.:

AF XY:

0.00512

AC XY:

381

AN XY:

74442

show subpopulations

Gnomad4 AFR

AF:

0.00118

Gnomad4 AMR

AF:

0.00706

Gnomad4 ASJ

AF:

0.0355

Gnomad4 EAS

AF:

0.000194

Gnomad4 SAS

AF:

0.00145

Gnomad4 FIN

AF:

0.00235

Gnomad4 NFE

AF:

0.00685

Gnomad4 OTH

AF:

0.00902

Alfa

AF:

0.00619

Hom.:

Bravo

AF:

0.00521

TwinsUK

AF:

0.00782

AC:

ALSPAC

AF:

0.00701

AC:

ESP6500AA

AF:

0.000909

AC:

ESP6500EA

AF:

0.00756

AC:

ExAC

AF:

0.00507

AC:

615

Asia WGS

AF:

0.00115

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Jan 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CYP4F8: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.093

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.46

CADD

Benign

1.2

DANN

Benign

0.92

DEOGEN2

Benign

0.086

.;T

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.011

LIST_S2

Benign

0.20

T;T

MetaRNN

Benign

0.0040

T;T

MetaSVM

Benign

-0.99

PrimateAI

Benign

0.23

Sift4G

Benign

0.54

T;T

Polyphen

0.055

.;B

Vest4

0.071

MVP

0.055

ClinPred

0.015

GERP RS

-4.6

Varity_R

0.029

gMVP

0.25

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over