rs6956344

Variant names:

• chr7-99761528-C-T
• rs6956344
• NM_017460.6:c.1253+513G>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.1253+513G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.159 in 151,932 control chromosomes in the GnomAD database, including 2,829 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 0.16 (2829 hom., cov: 31)
• Consequence: CYP3A4 NM_017460.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.649
• Publications: 10 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=-0.84).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.326 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP3A4	NM_017460.6	c.1253+513G>A		intron_variant	Intron 11 of 12	ENST00000651514.1	NP_059488.2
CYP3A4	NM_001202855.3	c.1250+513G>A		intron_variant	Intron 11 of 12		NP_001189784.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP3A4	ENST00000651514.1	c.1253+513G>A		intron_variant	Intron 11 of 12		NM_017460.6	ENSP00000498939.1

Frequencies

GnomAD3 genomes AF: 0.159 AC: 24154 AN: 151812 Hom.: 2829 Cov.: 31

Gnomad AFR AF: 0.331

Gnomad AMI AF: 0.0713

Gnomad AMR AF: 0.122

Gnomad ASJ AF: 0.0915

Gnomad EAS AF: 0.0400

Gnomad SAS AF: 0.109

Gnomad FIN AF: 0.0905

Gnomad MID AF: 0.185

Gnomad NFE AF: 0.0913

Gnomad OTH AF: 0.151

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

GnomAD4 genome AF: 0.159 AC: 24172 AN: 151932 Hom.: 2829 Cov.: 31 AF XY: 0.155 AC XY: 11517 AN XY: 74268

African (AFR) AF: 0.331 AC: 13682 AN: 41338

American (AMR) AF: 0.121 AC: 1852 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.0915 AC: 317 AN: 3466

East Asian (EAS) AF: 0.0401 AC: 208 AN: 5186

South Asian (SAS) AF: 0.109 AC: 521 AN: 4792

European-Finnish (FIN) AF: 0.0905 AC: 958 AN: 10588

Middle Eastern (MID) AF: 0.167 AC: 49 AN: 294

European-Non Finnish (NFE) AF: 0.0912 AC: 6203 AN: 67984

Other (OTH) AF: 0.151 AC: 317 AN: 2106

Alfa AF: 0.119 Hom.: 2225

Bravo AF: 0.168

Asia WGS AF: 0.106 AC: 369 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	1.7
DANN	Benign	0.31
PhyloP100		-0.65
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: rs6956344; hg19: chr7-99359151;