chr7-99764003-A-G

Variant names:

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2

The NM_017460.6(CYP3A4):c.878T>C(p.Leu293Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000629 in 1,613,998 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.00091 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00060 ( 17 hom. )

Consequence

CYP3A4
NM_017460.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.89

Variant links:

Genes affected

CYP3A4 (HGNC:2637): (cytochrome P450 family 3 subfamily A member 4) This gene encodes a member of the cytochrome P450 superfamily of enzymes. The cytochrome P450 proteins are monooxygenases that catalyze many reactions involved in drug metabolism and synthesis of cholesterol, steroids and other lipids. This protein localizes to the endoplasmic reticulum and its expression is induced by glucocorticoids and some pharmacological agents. This enzyme is involved in the metabolism of approximately half the drugs in use today, including acetaminophen, codeine, cyclosporin A, diazepam, erythromycin, and chloroquine. The enzyme also metabolizes some steroids and carcinogens. This gene is part of a cluster of cytochrome P450 genes on chromosome 7q21.1. Previously another CYP3A gene, CYP3A3, was thought to exist; however, it is now thought that this sequence represents a transcript variant of CYP3A4. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Aug 2020]

CYP3A4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0077759027).

BS1

Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.000599 (876/1461642) while in subpopulation EAS AF= 0.0174 (691/39676). AF 95% confidence interval is 0.0163. There are 17 homozygotes in gnomad4_exome. There are 422 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAd4 at 139 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP3A4	NM_017460.6 link	c.878T>C	p.Leu293Pro	missense_variant	Exon 10 of 13	ENST00000651514.1	NP_059488.2	P08684Q6GRK0
CYP3A4	NM_001202855.3 link	c.875T>C	p.Leu292Pro	missense_variant	Exon 10 of 13		NP_001189784.1	P08684Q6GRK0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP3A4	ENST00000651514.1 link	c.878T>C	p.Leu293Pro	missense_variant	Exon 10 of 13		NM_017460.6	ENSP00000498939.1		P08684

Frequencies

GnomAD3 genomes

AF:

0.000913

AC:

139

AN:

152238

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00104

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0171

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00239

GnomAD3 exomes

AF:

0.00155

AC:

390

AN:

250996

Hom.:

AF XY:

0.00145

AC XY:

197

AN XY:

135644

show subpopulations

Gnomad AFR exome

AF:

0.00142

Gnomad AMR exome

AF:

0.0000868

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0191

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00196

GnomAD4 exome

AF:

0.000599

AC:

876

AN:

1461642

Hom.:

Cov.:

AF XY:

0.000580

AC XY:

422

AN XY:

727136

show subpopulations

Gnomad4 AFR exome

AF:

0.000717

Gnomad4 AMR exome

AF:

0.0000895

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0174

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.00257

GnomAD4 genome

AF:

0.000912

AC:

139

AN:

152356

Hom.:

Cov.:

AF XY:

0.000899

AC XY:

AN XY:

74510

show subpopulations

Gnomad4 AFR

AF:

0.00103

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.0172

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00236

Alfa

AF:

0.000523

Hom.:

Bravo

AF:

0.00127

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00182

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00147

AC:

178

Asia WGS

AF:

0.00924

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Vitamin D-dependent rickets, type 3

Uncertain:1

Jun 11, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.24

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.41

CADD

Benign

DANN

Benign

0.94

DEOGEN2

Benign

0.025

T;T

Eigen

Benign

-0.72

Eigen_PC

Benign

-0.81

FATHMM_MKL

Benign

0.059

LIST_S2

Benign

0.78

T;T

MetaRNN

Benign

0.0078

T;T

MetaSVM

Benign

-0.88

MutationAssessor

Uncertain

2.1

.;M

PrimateAI

Benign

0.31

PROVEAN

Uncertain

-3.1

D;D

REVEL

Benign

0.13

Sift

Benign

0.27

T;T

Sift4G

Benign

0.26

T;T

Polyphen

0.47

P;B

Vest4

0.36

MVP

0.39

MPC

0.14

ClinPred

0.047

GERP RS

-1.2

Varity_R

0.80

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