rs28988579

Positions:

• chr7-99771076-A-C
• chr7-99771076-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_017460.6(CYP3A4):​c.319-841T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.026 in 152,294 control chromosomes in the GnomAD database, including 83 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 0.026 (83 hom., cov: 32)
• Consequence: CYP3A4 NM_017460.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0250

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=-0.87).
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.026 (3954/152294) while in subpopulation SAS AF= 0.0543 (262/4822). AF 95% confidence interval is 0.0489. There are 83 homozygotes in gnomad4. There are 1952 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 3954 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYP3A4	NM_017460.6	c.319-841T>G		intron_variant		ENST00000651514.1	NP_059488.2
CYP3A4	NM_001202855.3	c.319-841T>G		intron_variant			NP_001189784.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYP3A4	ENST00000651514.1	c.319-841T>G		intron_variant			NM_017460.6	ENSP00000498939	P1

Frequencies

GnomAD3 genomes AF: 0.0260 AC: 3951 AN: 152176 Hom.: 83 Cov.: 32

Gnomad AFR AF: 0.00634

Gnomad AMI AF: 0.0463

Gnomad AMR AF: 0.0270

Gnomad ASJ AF: 0.0467

Gnomad EAS AF: 0.000576

Gnomad SAS AF: 0.0539

Gnomad FIN AF: 0.0221

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.0365

Gnomad OTH AF: 0.0368

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

GnomAD4 genome AF: 0.0260 AC: 3954 AN: 152294 Hom.: 83 Cov.: 32 AF XY: 0.0262 AC XY: 1952 AN XY: 74470

Gnomad4 AFR AF: 0.00633

Gnomad4 AMR AF: 0.0269

Gnomad4 ASJ AF: 0.0467

Gnomad4 EAS AF: 0.000578

Gnomad4 SAS AF: 0.0543

Gnomad4 FIN AF: 0.0221

Gnomad4 NFE AF: 0.0366

Gnomad4 OTH AF: 0.0364

Alfa AF: 0.0233 Hom.: 10

Bravo AF: 0.0243

Asia WGS AF: 0.0190 AC: 64 AN: 3472

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	6.2
DANN	Benign	0.84

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: rs28988579; hg19: chr7-99368699;