rs17161886

Variant names:

• chr7-99758701-A-C
• rs17161886
• NM_017460.6:c.1417-473T>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_017460.6(CYP3A4):​c.1417-473T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0911 in 152,172 control chromosomes in the GnomAD database, including 2,073 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 0.091 (2073 hom., cov: 32)
• Consequence: CYP3A4 NM_017460.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -4.11
• Publications: 4 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.0).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.31 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP3A4	NM_017460.6	c.1417-473T>G		intron_variant	Intron 12 of 12	ENST00000651514.1	NP_059488.2
CYP3A4	NM_001202855.3	c.1414-473T>G		intron_variant	Intron 12 of 12		NP_001189784.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP3A4	ENST00000651514.1	c.1417-473T>G		intron_variant	Intron 12 of 12		NM_017460.6	ENSP00000498939.1

Frequencies

GnomAD3 genomes AF: 0.0910 AC: 13839 AN: 152054 Hom.: 2071 Cov.: 32

Gnomad AFR AF: 0.314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0380

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0102

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.00103

Gnomad OTH AF: 0.0669

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

GnomAD4 genome AF: 0.0911 AC: 13868 AN: 152172 Hom.: 2073 Cov.: 32 AF XY: 0.0882 AC XY: 6564 AN XY: 74392

African (AFR) AF: 0.314 AC: 13021 AN: 41438

American (AMR) AF: 0.0379 AC: 580 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5184

South Asian (SAS) AF: 0.00996 AC: 48 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.00103 AC: 70 AN: 68018

Other (OTH) AF: 0.0672 AC: 142 AN: 2114

Alfa AF: 0.0236 Hom.: 612

Bravo AF: 0.105

Asia WGS AF: 0.0190 AC: 69 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.067
DANN	Benign	0.47
PhyloP100		-4.1
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: rs17161886; hg19: chr7-99356324;