Genetic Variant CYP3A4:p.Leu293Gln (chr7-99764003-A-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_017460.6(CYP3A4):c.878T>A(p.Leu293Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 17/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L293P) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

CYP3A4
NM_017460.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.89

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

vitamin D-dependent rickets, type 3
Inheritance: AD, Unknown Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

CYP3A4 links:

CYP3A4-AS1 (HGNC:58107):

CYP3A4-AS1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.042922944).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017460.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CYP3A4	NM_017460.6	MANE Select	c.878T>A	p.Leu293Gln	missense	Exon 10 of 13	NP_059488.2
CYP3A4	NM_001202855.3		c.875T>A	p.Leu292Gln	missense	Exon 10 of 13	NP_001189784.1
CYP3A4-AS1	NR_198962.1		n.72A>T		non_coding_transcript_exon	Exon 1 of 1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CYP3A4	ENST00000651514.1	MANE Select	c.878T>A	p.Leu293Gln	missense	Exon 10 of 13	ENSP00000498939.1	P08684
CYP3A4	ENST00000336411.7	TSL:1	c.878T>A	p.Leu293Gln	missense	Exon 10 of 14	ENSP00000337915.3	A0A499FJM4
CYP3A4	ENST00000859201.1		c.875T>A	p.Leu292Gln	missense	Exon 10 of 14	ENSP00000529260.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.50

CADD

Benign

(source)

DANN

Benign

0.47

DEOGEN2

Benign

0.0069

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.015

LIST_S2

Benign

0.79

M_CAP

Benign

0.0045

MetaRNN

Benign

0.043

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.7

PhyloP100

-1.9

PrimateAI

Benign

0.29

PROVEAN

Benign

-1.8

REVEL

Benign

0.087

Sift

Benign

0.60

Sift4G

Benign

0.57

Polyphen

0.0020

Vest4

0.16

MutPred

0.29

Gain of solvent accessibility (P = 0.0216)

MVP

0.28

MPC

0.086

ClinPred

0.056

GERP RS

-1.2

Varity_R

0.30

Mutation Taster

=86/14

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over