7-99769769-C-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_017460.6(CYP3A4):c.520G>C(p.Asp174His) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00383 in 1,613,948 control chromosomes in the GnomAD database, including 27 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/23 in silico tools predict 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. Synonymous variant affecting the same amino acid position (i.e. D174D) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0024 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0040 ( 26 hom. )

Consequence

CYP3A4
NM_017460.6 missense, splice_region

Scores

Splicing: ADA: 0.00004696

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.05

Publications

29 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: Unknown, AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

CYP3A4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.013969451).

BS2

High AC in GnomAd4 at 361 Unknown,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP3A4	NM_017460.6 link	c.520G>C	p.Asp174His	missense_variant, splice_region_variant	Exon 6 of 13	ENST00000651514.1	NP_059488.2
CYP3A4	NM_001202855.3 link	c.520G>C	p.Asp174His	missense_variant, splice_region_variant	Exon 6 of 13		NP_001189784.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP3A4	ENST00000651514.1 link	c.520G>C	p.Asp174His	missense_variant, splice_region_variant	Exon 6 of 13		NM_017460.6	ENSP00000498939.1

Frequencies

GnomAD3 genomes

AF:

0.00237

AC:

361

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00145

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.000916

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.000829

Gnomad FIN

AF:

0.000659

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00398

Gnomad OTH

AF:

0.00143

GnomAD2 exomes

AF:

0.00195

AC:

490

AN:

251268

AF XY:

0.00201

show subpopulations

Gnomad AFR exome

AF:

0.00123

Gnomad AMR exome

AF:

0.000752

Gnomad ASJ exome

AF:

0.0000993

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.000462

Gnomad NFE exome

AF:

0.00323

Gnomad OTH exome

AF:

0.00359

GnomAD4 exome

AF:

0.00398

AC:

5818

AN:

1461640

Hom.:

Cov.:

AF XY:

0.00379

AC XY:

2759

AN XY:

727126

show subpopulations

African (AFR)

AF:

0.00129

AC:

AN:

33456

American (AMR)

AF:

0.000895

AC:

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26126

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00136

AC:

117

AN:

86256

European-Finnish (FIN)

AF:

0.000487

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.000694

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.00483

AC:

5373

AN:

1111834

Other (OTH)

AF:

0.00354

AC:

214

AN:

60376

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

300

601

901

1202

1502

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

216

432

648

864

1080

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00237

AC:

361

AN:

152308

Hom.:

Cov.:

AF XY:

0.00193

AC XY:

144

AN XY:

74486

show subpopulations

African (AFR)

AF:

0.00144

AC:

AN:

41572

American (AMR)

AF:

0.000915

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5170

South Asian (SAS)

AF:

0.000829

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.000659

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00398

AC:

271

AN:

68022

Other (OTH)

AF:

0.00142

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000508

Hom.:

Bravo

AF:

0.00221

TwinsUK

AF:

0.00458

AC:

ALSPAC

AF:

0.00363

AC:

ESP6500AA

AF:

0.00227

AC:

ESP6500EA

AF:

0.00360

AC:

ExAC

AF:

0.00172

AC:

209

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.00398

EpiControl

AF:

0.00439

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.37

CADD

Benign

(source)

DANN

Benign

0.93

DEOGEN2

Uncertain

0.48

Eigen

Benign

-0.22

Eigen_PC

Benign

-0.22

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.43

M_CAP

Benign

0.025

MetaRNN

Benign

0.014

MetaSVM

Benign

-0.66

MutationAssessor

Pathogenic

3.4

PhyloP100

1.1

PrimateAI

Benign

0.42

PROVEAN

Uncertain

-3.8

REVEL

Benign

0.15

Sift

Benign

0.079

Sift4G

Uncertain

0.043

Polyphen

0.0080

Vest4

0.33

MVP

0.81

MPC

0.11

ClinPred

0.076

GERP RS

2.8

Varity_R

0.33

Mutation Taster

=32/68

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000047

dbscSNV1_RF

Benign

0.0020

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over