rs2242480

Positions:

• chr7-99763843-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_017460.6(CYP3A4):​c.1026+12G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.153 in 1,613,368 control chromosomes in the GnomAD database, including 39,387 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as drug response (★★★).

• Frequency:
  • Genomes: 𝑓 0.31 (13270 hom., cov: 32)
  • Exomes 𝑓: 0.14 (26117 hom.)
• Consequence: CYP3A4 NM_017460.6 intron
• Clinical Significance: drug response reviewed by expert panel O:2
• Conservation: PhyloP100: -2.31

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.726 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYP3A4	NM_017460.6	c.1026+12G>A		intron_variant		ENST00000651514.1	NP_059488.2
CYP3A4	NM_001202855.3	c.1023+12G>A		intron_variant			NP_001189784.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYP3A4	ENST00000651514.1	c.1026+12G>A		intron_variant			NM_017460.6	ENSP00000498939	P1

Frequencies

GnomAD3 genomes AF: 0.310 AC: 47072 AN: 151980 Hom.: 13221 Cov.: 32

Gnomad AFR AF: 0.732

Gnomad AMI AF: 0.0713

Gnomad AMR AF: 0.358

Gnomad ASJ AF: 0.107

Gnomad EAS AF: 0.266

Gnomad SAS AF: 0.346

Gnomad FIN AF: 0.0773

Gnomad MID AF: 0.228

Gnomad NFE AF: 0.0938

Gnomad OTH AF: 0.282

GnomAD3 exomes AF: 0.224 AC: 56141 AN: 250424 Hom.: 10944 AF XY: 0.209 AC XY: 28306 AN XY: 135360

Gnomad AFR exome AF: 0.741

Gnomad AMR exome AF: 0.427

Gnomad ASJ exome AF: 0.105

Gnomad EAS exome AF: 0.263

Gnomad SAS exome AF: 0.329

Gnomad FIN exome AF: 0.0788

Gnomad NFE exome AF: 0.0958

Gnomad OTH exome AF: 0.169

GnomAD4 exome AF: 0.137 AC: 200071 AN: 1461268 Hom.: 26117 Cov.: 32 AF XY: 0.139 AC XY: 100880 AN XY: 726938

Gnomad4 AFR exome AF: 0.752

Gnomad4 AMR exome AF: 0.414

Gnomad4 ASJ exome AF: 0.103

Gnomad4 EAS exome AF: 0.250

Gnomad4 SAS exome AF: 0.320

Gnomad4 FIN exome AF: 0.0824

Gnomad4 NFE exome AF: 0.0901

Gnomad4 OTH exome AF: 0.177

GnomAD4 genome AF: 0.310 AC: 47186 AN: 152100 Hom.: 13270 Cov.: 32 AF XY: 0.310 AC XY: 23012 AN XY: 74348

Gnomad4 AFR AF: 0.733

Gnomad4 AMR AF: 0.359

Gnomad4 ASJ AF: 0.107

Gnomad4 EAS AF: 0.266

Gnomad4 SAS AF: 0.346

Gnomad4 FIN AF: 0.0773

Gnomad4 NFE AF: 0.0938

Gnomad4 OTH AF: 0.283

Alfa AF: 0.155 Hom.: 1266

Bravo AF: 0.347

Asia WGS AF: 0.367 AC: 1274 AN: 3476

ClinVar

Significance: drug response

Submissions summary: Other:2

Revision: reviewed by expert panel

Submissions by phenotype

tacrolimus response - Metabolism/PK Other:1

drug response, reviewed by expert panel

curation

PharmGKB

Jan 20, 2023

PharmGKB Level of Evidence 2A: Variants in Level 2A clinical annotations are found in PharmGKB’s Tier 1 Very Important Pharmacogenes (VIPs). These variants are in known pharmacogenes, implying causation of drug phenotype is more likely. These clinical annotations describe variant-drug combinations with a moderate level of evidence supporting the association. For example, the association may be found in multiple cohorts, but there may be a minority of studies that do not support the majority assertion. Level 2A clinical annotations must be supported by at least two independent publications. Drug-variant association: Metabolism/PK

fentanyl response - Dosage Other:1

drug response, reviewed by expert panel

curation

PharmGKB

Jan 17, 2023

PharmGKB Level of Evidence 2A: Variants in Level 2A clinical annotations are found in PharmGKB’s Tier 1 Very Important Pharmacogenes (VIPs). These variants are in known pharmacogenes, implying causation of drug phenotype is more likely. These clinical annotations describe variant-drug combinations with a moderate level of evidence supporting the association. For example, the association may be found in multiple cohorts, but there may be a minority of studies that do not support the majority assertion. Level 2A clinical annotations must be supported by at least two independent publications. Drug-variant association: Dosage

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.061
DANN	Benign	0.41

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

Other links and lift over

dbSNP: rs2242480; hg19: chr7-99361466; COSMIC: COSV60501030; COSMIC: COSV60501030;