chr7-99784473-C-T

Variant names:

• chr7-99784473-C-T
• rs2740574
• ENST00000859201.1:c.-392G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The ENST00000859201.1(CYP3A4):​c.-392G>A variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.791 in 151,898 control chromosomes in the GnomAD database, including 53,022 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.79 (53022 hom., cov: 31)
• Consequence: CYP3A4 ENST00000859201.1 upstream_gene
• Clinical Significance: Benign criteria provided, single submitter B:3
• Conservation: PhyloP100: -0.00600
• Publications: 437 publications found

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

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 7-99784473-C-T is Benign according to our data. Variant chr7-99784473-C-T is described in ClinVar as Benign. ClinVar VariationId is 16916.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.975 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000859201.1. 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
There are no transcript annotations for this variant.

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP3A4	ENST00000859201.1		c.-392G>A		upstream_gene	N/A	ENSP00000529260.1
	CYP3A4	ENST00000859200.1		c.-392G>A		upstream_gene	N/A	ENSP00000529259.1
	CYP3A4	ENST00000652018.1		c.-392G>A		upstream_gene	N/A	ENSP00000498733.1

Frequencies

GnomAD3 genomes AF: 0.791 AC: 120052 AN: 151780 Hom.: 53019 Cov.: 31

Gnomad AFR AF: 0.359

Gnomad AMI AF: 0.911

Gnomad AMR AF: 0.887

Gnomad ASJ AF: 0.954

Gnomad EAS AF: 0.998

Gnomad SAS AF: 0.970

Gnomad FIN AF: 0.963

Gnomad MID AF: 0.918

Gnomad NFE AF: 0.965

Gnomad OTH AF: 0.841

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.791 AC: 120086 AN: 151898 Hom.: 53022 Cov.: 31 AF XY: 0.797 AC XY: 59223 AN XY: 74270

African (AFR) AF: 0.359 AC: 14869 AN: 41432

American (AMR) AF: 0.887 AC: 13556 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.954 AC: 3305 AN: 3466

East Asian (EAS) AF: 0.998 AC: 5174 AN: 5184

South Asian (SAS) AF: 0.970 AC: 4659 AN: 4804

European-Finnish (FIN) AF: 0.963 AC: 10178 AN: 10568

Middle Eastern (MID) AF: 0.922 AC: 271 AN: 294

European-Non Finnish (NFE) AF: 0.965 AC: 65477 AN: 67860

Other (OTH) AF: 0.841 AC: 1768 AN: 2102

Alfa AF: 0.885 Hom.: 127041

Bravo AF: 0.765

Asia WGS AF: 0.938 AC: 3261 AN: 3476

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	CYP3A4 PROMOTER POLYMORPHISM (1)
-	-	1	CYP3A4-V (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	6.2
DANN	Benign	0.60
PhyloP100		-0.0060
PromoterAI		-0.0016	Neutral

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2740574; hg19: chr7-99382096;