Genetic Variant CYP3A4:c.*767delT (chr7-99757365-CA-C) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

The NM_017460.6(CYP3A4):c.*767delT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.258 in 152,008 control chromosomes in the GnomAD database, including 7,933 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.26 ( 7932 hom., cov: 26)

Exomes 𝑓: 0.075 ( 1 hom. )

Consequence

CYP3A4
NM_017460.6 3_prime_UTR

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.00

Publications

3 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.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.549 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP3A4	NM_017460.6	MANE Select	c.*767delT		3_prime_UTR	Exon 13 of 13	NP_059488.2
	CYP3A4	NM_001202855.3		c.*767delT		3_prime_UTR	Exon 13 of 13	NP_001189784.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
CYP3A4	ENST00000651514.1	MANE Select	c.*767delT	3_prime_UTR	Exon 13 of 13	ENSP00000498939.1
CYP3A4	ENST00000859201.1		c.*767delT	3_prime_UTR	Exon 14 of 14	ENSP00000529260.1
CYP3A4	ENST00000859200.1		c.*767delT	3_prime_UTR	Exon 13 of 13	ENSP00000529259.1

Frequencies

GnomAD3 genomes

AF:

0.258

AC:

39121

AN:

151850

Hom.:

7917

Cov.:

show subpopulations

Gnomad AFR

AF:

0.556

Gnomad AMI

AF:

0.0713

Gnomad AMR

AF:

0.234

Gnomad ASJ

AF:

0.116

Gnomad EAS

AF:

0.297

Gnomad SAS

AF:

0.349

Gnomad FIN

AF:

0.109

Gnomad MID

AF:

0.201

Gnomad NFE

AF:

0.106

Gnomad OTH

AF:

0.241

GnomAD4 exome

AF:

0.0750

AC:

AN:

Hom.:

Cov.:

AF XY:

0.115

AC XY:

AN XY:

show subpopulations

African (AFR)

AC:

AN:

American (AMR)

AF:

0.00

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.0789

AC:

AN:

Other (OTH)

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.258

AC:

39179

AN:

151968

Hom.:

7932

Cov.:

AF XY:

0.259

AC XY:

19254

AN XY:

74258

show subpopulations

African (AFR)

AF:

0.556

AC:

22988

AN:

41382

American (AMR)

AF:

0.234

AC:

3571

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.116

AC:

401

AN:

3468

East Asian (EAS)

AF:

0.298

AC:

1533

AN:

5152

South Asian (SAS)

AF:

0.348

AC:

1675

AN:

4808

European-Finnish (FIN)

AF:

0.109

AC:

1150

AN:

10576

Middle Eastern (MID)

AF:

0.188

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.106

AC:

7229

AN:

67984

Other (OTH)

AF:

0.242

AC:

512

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1196

2393

3589

4786

5982

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

370

740

1110

1480

1850

<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:

0.191

Hom.:

607

Bravo

AF:

0.279

Asia WGS

AF:

0.357

AC:

1242

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.0

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over