chr7-99779323-A-T

Position:

• chr7-99779323-A-T

Variant summary

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

The NM_017460.6(CYP3A4):​c.165+669T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.791 in 152,034 control chromosomes in the GnomAD database, including 53,162 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 0.79 (53162 hom., cov: 31)
• Consequence: CYP3A4 NM_017460.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.657

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=-0.91).
• 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	Protein	UniProt
CYP3A4	NM_017460.6	c.165+669T>A		intron_variant		ENST00000651514.1	NP_059488.2
CYP3A4	NM_001202855.3	c.165+669T>A		intron_variant			NP_001189784.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYP3A4	ENST00000651514.1	c.165+669T>A		intron_variant			NM_017460.6	ENSP00000498939	P1

Frequencies

GnomAD3 genomes AF: 0.792 AC: 120296 AN: 151916 Hom.: 53157 Cov.: 31

Gnomad AFR AF: 0.360

Gnomad AMI AF: 0.912

Gnomad AMR AF: 0.888

Gnomad ASJ AF: 0.954

Gnomad EAS AF: 0.998

Gnomad SAS AF: 0.970

Gnomad FIN AF: 0.964

Gnomad MID AF: 0.918

Gnomad NFE AF: 0.965

Gnomad OTH AF: 0.842

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

GnomAD4 genome AF: 0.791 AC: 120334 AN: 152034 Hom.: 53162 Cov.: 31 AF XY: 0.798 AC XY: 59338 AN XY: 74326

Gnomad4 AFR AF: 0.360

Gnomad4 AMR AF: 0.888

Gnomad4 ASJ AF: 0.954

Gnomad4 EAS AF: 0.998

Gnomad4 SAS AF: 0.970

Gnomad4 FIN AF: 0.964

Gnomad4 NFE AF: 0.965

Gnomad4 OTH AF: 0.842

Alfa AF: 0.862 Hom.: 6977

Bravo AF: 0.765

Asia WGS AF: 0.939 AC: 3264 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	10
DANN	Benign	0.56

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: rs2687105; hg19: chr7-99376946;