7-99763247-G-A

Variant names:

• chr7-99763247-G-A
• rs4646440
• NM_017460.6:c.1026+608C>T

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+608C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0552 in 152,160 control chromosomes in the GnomAD database, including 725 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 0.055 (725 hom., cov: 32)
• Consequence: CYP3A4 NM_017460.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.590
• Publications: 31 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=-0.86).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.224 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP3A4	NM_017460.6	c.1026+608C>T		intron_variant	Intron 10 of 12	ENST00000651514.1	NP_059488.2
CYP3A4	NM_001202855.3	c.1023+608C>T		intron_variant	Intron 10 of 12		NP_001189784.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP3A4	ENST00000651514.1	c.1026+608C>T		intron_variant	Intron 10 of 12		NM_017460.6	ENSP00000498939.1

Frequencies

GnomAD3 genomes AF: 0.0551 AC: 8375 AN: 152042 Hom.: 719 Cov.: 32

Gnomad AFR AF: 0.0724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.177

Gnomad ASJ AF: 0.0115

Gnomad EAS AF: 0.224

Gnomad SAS AF: 0.236

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00337

Gnomad OTH AF: 0.0536

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

GnomAD4 genome AF: 0.0552 AC: 8401 AN: 152160 Hom.: 725 Cov.: 32 AF XY: 0.0617 AC XY: 4589 AN XY: 74384

African (AFR) AF: 0.0724 AC: 3005 AN: 41498

American (AMR) AF: 0.178 AC: 2716 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0115 AC: 40 AN: 3472

East Asian (EAS) AF: 0.224 AC: 1156 AN: 5160

South Asian (SAS) AF: 0.236 AC: 1136 AN: 4818

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10612

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00337 AC: 229 AN: 67994

Other (OTH) AF: 0.0545 AC: 115 AN: 2112

Alfa AF: 0.0249 Hom.: 843

Bravo AF: 0.0651

Asia WGS AF: 0.228 AC: 793 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	1.5
DANN	Benign	0.33
PhyloP100		0.59
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: rs4646440; hg19: chr7-99360870;