rs28988604

Positions:

• chr7-99757450-G-A
• chr7-99757450-G-C

Variant summary

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

The NM_017460.6(CYP3A4):​c.*683C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0292 in 152,500 control chromosomes in the GnomAD database, including 91 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 0.029 (91 hom., cov: 32)
  • Exomes 𝑓: 0.012 (0 hom.)
• Consequence: CYP3A4 NM_017460.6 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0480

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=-1.03).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0527 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYP3A4	NM_017460.6	c.*683C>T		3_prime_UTR_variant	13/13	ENST00000651514.1	NP_059488.2
CYP3A4	NM_001202855.3	c.*683C>T		3_prime_UTR_variant	13/13		NP_001189784.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYP3A4	ENST00000651514	c.*683C>T		3_prime_UTR_variant	13/13		NM_017460.6	ENSP00000498939.1
CYP3A4	ENST00000354593	c.*683C>T		3_prime_UTR_variant	8/8	5		ENSP00000346607.2

Frequencies

GnomAD3 genomes AF: 0.0292 AC: 4435 AN: 152124 Hom.: 90 Cov.: 32

Gnomad AFR AF: 0.0546

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0323

Gnomad ASJ AF: 0.0132

Gnomad EAS AF: 0.00135

Gnomad SAS AF: 0.00644

Gnomad FIN AF: 0.0406

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0161

Gnomad OTH AF: 0.0302

GnomAD4 exome AF: 0.0116 AC: 3 AN: 258 Hom.: 0 Cov.: 0 AF XY: 0.0120 AC XY: 2 AN XY: 166

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0135

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0292 AC: 4449 AN: 152242 Hom.: 91 Cov.: 32 AF XY: 0.0297 AC XY: 2208 AN XY: 74430

Gnomad4 AFR AF: 0.0546

Gnomad4 AMR AF: 0.0323

Gnomad4 ASJ AF: 0.0132

Gnomad4 EAS AF: 0.00135

Gnomad4 SAS AF: 0.00644

Gnomad4 FIN AF: 0.0406

Gnomad4 NFE AF: 0.0161

Gnomad4 OTH AF: 0.0327

Alfa AF: 0.00986 Hom.: 1

Bravo AF: 0.0310

Asia WGS AF: 0.0120 AC: 41 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	1.4
DANN	Benign	0.41

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs28988604; hg19: chr7-99355073;