chr7-99758352-T-C

Variant names:

• chr7-99758352-T-C
• rs3735451
• NM_017460.6:c.1417-124A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_017460.6(CYP3A4):​c.1417-124A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.17 in 1,177,246 control chromosomes in the GnomAD database, including 31,124 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 0.30 (12103 hom., cov: 32)
  • Exomes 𝑓: 0.15 (19021 hom.)
• Consequence: CYP3A4 NM_017460.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.56
• Publications: 42 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=-0.98).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.698 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.1417-124A>G		intron	N/A	NP_059488.2
	CYP3A4	NM_001202855.3		c.1414-124A>G		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.1417-124A>G		intron	N/A	ENSP00000498939.1	P08684
	CYP3A4	ENST00000336411.7	TSL:1	c.1510-124A>G		intron	N/A	ENSP00000337915.3	A0A499FJM4
	CYP3A4	ENST00000859201.1		c.1507-124A>G		intron	N/A	ENSP00000529260.1

Frequencies

GnomAD3 genomes AF: 0.302 AC: 45859 AN: 151748 Hom.: 12064 Cov.: 32

Gnomad AFR AF: 0.704

Gnomad AMI AF: 0.0716

Gnomad AMR AF: 0.259

Gnomad ASJ AF: 0.116

Gnomad EAS AF: 0.299

Gnomad SAS AF: 0.351

Gnomad FIN AF: 0.109

Gnomad MID AF: 0.228

Gnomad NFE AF: 0.108

Gnomad OTH AF: 0.276

GnomAD4 exome AF: 0.151 AC: 154647 AN: 1025380 Hom.: 19021 AF XY: 0.155 AC XY: 80956 AN XY: 523298

African (AFR) AF: 0.721 AC: 17590 AN: 24400

American (AMR) AF: 0.274 AC: 9945 AN: 36294

Ashkenazi Jewish (ASJ) AF: 0.116 AC: 2596 AN: 22370

East Asian (EAS) AF: 0.277 AC: 10016 AN: 36156

South Asian (SAS) AF: 0.326 AC: 23891 AN: 73372

European-Finnish (FIN) AF: 0.115 AC: 4827 AN: 41950

Middle Eastern (MID) AF: 0.182 AC: 594 AN: 3264

European-Non Finnish (NFE) AF: 0.104 AC: 76926 AN: 742106

Other (OTH) AF: 0.182 AC: 8262 AN: 45468

GnomAD4 genome AF: 0.303 AC: 45958 AN: 151866 Hom.: 12103 Cov.: 32 AF XY: 0.303 AC XY: 22467 AN XY: 74244

African (AFR) AF: 0.705 AC: 29210 AN: 41436

American (AMR) AF: 0.259 AC: 3949 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.116 AC: 401 AN: 3462

East Asian (EAS) AF: 0.299 AC: 1533 AN: 5130

South Asian (SAS) AF: 0.351 AC: 1682 AN: 4794

European-Finnish (FIN) AF: 0.109 AC: 1152 AN: 10580

Middle Eastern (MID) AF: 0.211 AC: 62 AN: 294

European-Non Finnish (NFE) AF: 0.108 AC: 7318 AN: 67884

Other (OTH) AF: 0.277 AC: 586 AN: 2116

Alfa AF: 0.170 Hom.: 17039

Bravo AF: 0.328

Asia WGS AF: 0.373 AC: 1296 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	0.67
DANN	Benign	0.39
PhyloP100		-1.6
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: rs3735451; hg19: chr7-99355975;