rs2246709

chr7-99768096-A-G

Variant summary

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

The NM_017460.6(CYP3A4):c.670+258T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.316 in 152,066 control chromosomes in the GnomAD database, including 7,734 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.32 (7734 hom., cov: 32)
• Consequence: CYP3A4 NM_017460.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.211

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=-0.9).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.408 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYP3A4	NM_017460.6	c.670+258T>C		intron_variant		ENST00000651514.1
CYP3A4	NM_001202855.3	c.670+258T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP3A4	ENST00000651514.1	c.670+258T>C		intron_variant			NM_017460.6	P1
CYP3A4	ENST00000336411.7	c.670+258T>C		intron_variant		1
CYP3A4	ENST00000354593.6	c.220+258T>C		intron_variant		5
CYP3A4	ENST00000652018.1	c.523+258T>C		intron_variant

Frequencies

GnomAD3 genomes AF: 0.316 AC: 47959 AN: 151948 Hom.: 7716 Cov.: 32

Gnomad AFR AF: 0.345

Gnomad AMI AF: 0.238

Gnomad AMR AF: 0.416

Gnomad ASJ AF: 0.280

Gnomad EAS AF: 0.392

Gnomad SAS AF: 0.369

Gnomad FIN AF: 0.272

Gnomad MID AF: 0.206

Gnomad NFE AF: 0.276

Gnomad OTH AF: 0.321

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

GnomAD4 genome AF: 0.316 AC: 48030 AN: 152066 Hom.: 7734 Cov.: 32 AF XY: 0.320 AC XY: 23770 AN XY: 74356

Gnomad4 AFR AF: 0.345

Gnomad4 AMR AF: 0.416

Gnomad4 ASJ AF: 0.280

Gnomad4 EAS AF: 0.393

Gnomad4 SAS AF: 0.368

Gnomad4 FIN AF: 0.272

Gnomad4 NFE AF: 0.276

Gnomad4 OTH AF: 0.321

Alfa AF: 0.287 Hom.: 9283

Bravo AF: 0.327

Asia WGS AF: 0.413 AC: 1437 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
Cadd	Benign	1.4
Dann	Benign	0.45

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: rs2246709; hg19: chr7-99365719;