rs28969391

Positions:

• chr7-99757365-CA-C
• chr7-99757365-CA-CAA

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6 BA1

The NM_017460.6(CYP3A4):​c.*767delT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.258 in 152,008 control chromosomes in the GnomAD database, including 7,933 homozygotes. Variant has been reported in Lovd as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.26 (7932 hom., cov: 26)
  • Exomes 𝑓: 0.075 (1 hom.)
• Consequence: CYP3A4 NM_017460.6 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.00

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 -9 ACMG points.

• BP6: Variant 7-99757365-CA-C is Benign according to our data. Variant chr7-99757365-CA-C is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.549 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYP3A4	NM_017460.6	c.*767delT		3_prime_UTR_variant	13/13	ENST00000651514.1	NP_059488.2
CYP3A4	NM_001202855.3	c.*767delT		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.*767delT		3_prime_UTR_variant	13/13		NM_017460.6	ENSP00000498939.1
CYP3A4	ENST00000354593	c.*767delT		3_prime_UTR_variant	8/8	5		ENSP00000346607.2

Frequencies

GnomAD3 genomes AF: 0.258 AC: 39121 AN: 151850 Hom.: 7917 Cov.: 26

Gnomad AFR AF: 0.556

Gnomad AMI AF: 0.0713

Gnomad AMR AF: 0.234

Gnomad ASJ AF: 0.116

Gnomad EAS AF: 0.297

Gnomad SAS AF: 0.349

Gnomad FIN AF: 0.109

Gnomad MID AF: 0.201

Gnomad NFE AF: 0.106

Gnomad OTH AF: 0.241

GnomAD4 exome AF: 0.0750 AC: 3 AN: 40 Hom.: 1 Cov.: 0 AF XY: 0.115 AC XY: 3 AN XY: 26

Gnomad4 AMR exome AF: 0.00

Gnomad4 NFE exome AF: 0.0789

GnomAD4 genome AF: 0.258 AC: 39179 AN: 151968 Hom.: 7932 Cov.: 26 AF XY: 0.259 AC XY: 19254 AN XY: 74258

Gnomad4 AFR AF: 0.556

Gnomad4 AMR AF: 0.234

Gnomad4 ASJ AF: 0.116

Gnomad4 EAS AF: 0.298

Gnomad4 SAS AF: 0.348

Gnomad4 FIN AF: 0.109

Gnomad4 NFE AF: 0.106

Gnomad4 OTH AF: 0.242

Alfa AF: 0.191 Hom.: 607

Bravo AF: 0.279

Asia WGS AF: 0.357 AC: 1242 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs28969391; hg19: chr7-99354988;