chr7-99779323-A-T

Variant names:

• chr7-99779323-A-T
• rs2687105
• NM_017460.6:c.165+669T>A

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 4 publications found

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]

CYP3A4 Gene-Disease associations (from GenCC):

• vitamin D-dependent rickets, type 3

  Inheritance: Unknown, AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017460.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP3A4	NM_017460.6	MANE Select	c.165+669T>A		intron	N/A	NP_059488.2
	CYP3A4	NM_001202855.3		c.165+669T>A		intron	N/A	NP_001189784.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP3A4	ENST00000651514.1	MANE Select	c.165+669T>A		intron	N/A	ENSP00000498939.1
	CYP3A4	ENST00000336411.7	TSL:1	c.165+669T>A		intron	N/A	ENSP00000337915.3
	CYP3A4	ENST00000859201.1		c.165+669T>A		intron	N/A	ENSP00000529260.1

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

African (AFR) AF: 0.360 AC: 14869 AN: 41348

American (AMR) AF: 0.888 AC: 13565 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.954 AC: 3312 AN: 3472

East Asian (EAS) AF: 0.998 AC: 5174 AN: 5184

South Asian (SAS) AF: 0.970 AC: 4670 AN: 4814

European-Finnish (FIN) AF: 0.964 AC: 10221 AN: 10606

Middle Eastern (MID) AF: 0.922 AC: 271 AN: 294

European-Non Finnish (NFE) AF: 0.965 AC: 65640 AN: 68010

Other (OTH) AF: 0.842 AC: 1780 AN: 2114

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	10
DANN	Benign	0.56
PhyloP100		0.66
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2687105; hg19: chr7-99376946;