NM_017460.6:c.670+258T>C

Variant names:

• chr7-99768096-A-G
• rs2246709
• NM_017460.6:c.670+258T>C

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 57 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=-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 rank	MANE	Protein	UniProt
CYP3A4	NM_017460.6	c.670+258T>C		intron_variant	Intron 7 of 12	ENST00000651514.1	NP_059488.2
CYP3A4	NM_001202855.3	c.670+258T>C		intron_variant	Intron 7 of 12		NP_001189784.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP3A4	ENST00000651514.1	c.670+258T>C		intron_variant	Intron 7 of 12		NM_017460.6	ENSP00000498939.1
CYP3A4	ENST00000336411.7	c.670+258T>C		intron_variant	Intron 7 of 13	1		ENSP00000337915.3
CYP3A4	ENST00000652018.1	c.523+258T>C		intron_variant	Intron 5 of 10			ENSP00000498733.1
CYP3A4	ENST00000354593.6	c.220+258T>C		intron_variant	Intron 2 of 7	5		ENSP00000346607.2

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

African (AFR) AF: 0.345 AC: 14307 AN: 41462

American (AMR) AF: 0.416 AC: 6363 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.280 AC: 972 AN: 3468

East Asian (EAS) AF: 0.393 AC: 2030 AN: 5168

South Asian (SAS) AF: 0.368 AC: 1776 AN: 4826

European-Finnish (FIN) AF: 0.272 AC: 2881 AN: 10580

Middle Eastern (MID) AF: 0.214 AC: 63 AN: 294

European-Non Finnish (NFE) AF: 0.276 AC: 18742 AN: 67962

Other (OTH) AF: 0.321 AC: 679 AN: 2114

Alfa AF: 0.289 Hom.: 21797

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
PhyloP100		0.21
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: rs2246709; hg19: chr7-99365719;