rs2242480

Variant names:

• chr7-99763843-C-T
• rs2242480
• NM_017460.6:c.1026+12G>A

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 262 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

CYP3A4-AS1 (HGNC:58107):

ACMG classification

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
CYP3A4	NM_017460.6	c.1026+12G>A		intron_variant	Intron 10 of 12	ENST00000651514.1	NP_059488.2
CYP3A4	NM_001202855.3	c.1023+12G>A		intron_variant	Intron 10 of 12		NP_001189784.1
CYP3A4-AS1	NR_198962.1	n.-89C>T		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP3A4	ENST00000651514.1	c.1026+12G>A		intron_variant	Intron 10 of 12		NM_017460.6	ENSP00000498939.1

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

GnomAD2 exomes AF: 0.224 AC: 56141 AN: 250424 AF XY: 0.209

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 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

African (AFR) AF: 0.752 AC: 25159 AN: 33446

American (AMR) AF: 0.414 AC: 18490 AN: 44614

Ashkenazi Jewish (ASJ) AF: 0.103 AC: 2701 AN: 26122

East Asian (EAS) AF: 0.250 AC: 9909 AN: 39604

South Asian (SAS) AF: 0.320 AC: 27551 AN: 86188

European-Finnish (FIN) AF: 0.0824 AC: 4402 AN: 53398

Middle Eastern (MID) AF: 0.179 AC: 1028 AN: 5758

European-Non Finnish (NFE) AF: 0.0901 AC: 100172 AN: 1111764

Other (OTH) AF: 0.177 AC: 10659 AN: 60374

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

African (AFR) AF: 0.733 AC: 30375 AN: 41448

American (AMR) AF: 0.359 AC: 5475 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.107 AC: 373 AN: 3470

East Asian (EAS) AF: 0.266 AC: 1378 AN: 5172

South Asian (SAS) AF: 0.346 AC: 1664 AN: 4816

European-Finnish (FIN) AF: 0.0773 AC: 820 AN: 10602

Middle Eastern (MID) AF: 0.205 AC: 60 AN: 292

European-Non Finnish (NFE) AF: 0.0938 AC: 6379 AN: 68010

Other (OTH) AF: 0.283 AC: 597 AN: 2110

Alfa AF: 0.216 Hom.: 4661

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

Jan 20, 2023

PharmGKB

Significance: drug response

Review Status: reviewed by expert panel

Collection Method: curation

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

Jan 17, 2023

PharmGKB

Significance: drug response

Review Status: reviewed by expert panel

Collection Method: curation

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
PhyloP100		-2.3
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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