rs2687116

Positions:

• chr7-99768320-C-A
• chr7-99768320-C-G
• chr7-99768320-C-T

Variant summary

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

The NM_017460.6(CYP3A4):​c.670+34G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.935 in 1,597,134 control chromosomes in the GnomAD database, including 711,087 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 0.80 (53443 hom., cov: 32)
  • Exomes 𝑓: 0.95 (657644 hom.)
• Consequence: CYP3A4 NM_017460.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.04

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=-1.01).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.975 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYP3A4	NM_017460.6	c.670+34G>T		intron_variant		ENST00000651514.1
CYP3A4	NM_001202855.3	c.670+34G>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP3A4	ENST00000651514.1	c.670+34G>T		intron_variant			NM_017460.6	P1
CYP3A4	ENST00000336411.7	c.670+34G>T		intron_variant		1
CYP3A4	ENST00000354593.6	c.220+34G>T		intron_variant		5
CYP3A4	ENST00000652018.1	c.523+34G>T		intron_variant

Frequencies

GnomAD3 genomes AF: 0.799 AC: 121423 AN: 151954 Hom.: 53438 Cov.: 32

Gnomad AFR AF: 0.389

Gnomad AMI AF: 0.912

Gnomad AMR AF: 0.887

Gnomad ASJ AF: 0.949

Gnomad EAS AF: 0.997

Gnomad SAS AF: 0.961

Gnomad FIN AF: 0.964

Gnomad MID AF: 0.918

Gnomad NFE AF: 0.964

Gnomad OTH AF: 0.847

GnomAD3 exomes AF: 0.921 AC: 228420 AN: 248068 Hom.: 107881 AF XY: 0.933 AC XY: 125406 AN XY: 134348

Gnomad AFR exome AF: 0.370

Gnomad AMR exome AF: 0.918

Gnomad ASJ exome AF: 0.951

Gnomad EAS exome AF: 0.999

Gnomad SAS exome AF: 0.963

Gnomad FIN exome AF: 0.960

Gnomad NFE exome AF: 0.964

Gnomad OTH exome AF: 0.942

GnomAD4 exome AF: 0.949 AC: 1372018 AN: 1445060 Hom.: 657644 Cov.: 29 AF XY: 0.952 AC XY: 685206 AN XY: 719872

Gnomad4 AFR exome AF: 0.367

Gnomad4 AMR exome AF: 0.915

Gnomad4 ASJ exome AF: 0.951

Gnomad4 EAS exome AF: 0.999

Gnomad4 SAS exome AF: 0.964

Gnomad4 FIN exome AF: 0.959

Gnomad4 NFE exome AF: 0.966

Gnomad4 OTH exome AF: 0.928

GnomAD4 genome AF: 0.799 AC: 121456 AN: 152074 Hom.: 53443 Cov.: 32 AF XY: 0.806 AC XY: 59912 AN XY: 74348

Gnomad4 AFR AF: 0.389

Gnomad4 AMR AF: 0.887

Gnomad4 ASJ AF: 0.949

Gnomad4 EAS AF: 0.997

Gnomad4 SAS AF: 0.961

Gnomad4 FIN AF: 0.964

Gnomad4 NFE AF: 0.964

Gnomad4 OTH AF: 0.847

Alfa AF: 0.880 Hom.: 11728

Bravo AF: 0.773

Asia WGS AF: 0.935 AC: 3251 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	0.15
DANN	Benign	0.13

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: rs2687116; hg19: chr7-99365943;