7-99772870-T-C

Variant names:

• chr7-99772870-T-C
• rs2738258
• NM_017460.6:c.219-181A>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.219-181A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.903 in 152,068 control chromosomes in the GnomAD database, including 63,622 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 0.90 (63622 hom., cov: 30)
• Consequence: CYP3A4 NM_017460.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.947
• Publications: 6 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=-0.96).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.992 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP3A4	NM_017460.6	c.219-181A>G		intron_variant	Intron 3 of 12	ENST00000651514.1	NP_059488.2
CYP3A4	NM_001202855.3	c.219-181A>G		intron_variant	Intron 3 of 12		NP_001189784.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP3A4	ENST00000651514.1	c.219-181A>G		intron_variant	Intron 3 of 12		NM_017460.6	ENSP00000498939.1

Frequencies

GnomAD3 genomes AF: 0.903 AC: 137221 AN: 151950 Hom.: 63589 Cov.: 30

Gnomad AFR AF: 0.667

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.962

Gnomad ASJ AF: 0.993

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.987

Gnomad FIN AF: 1.00

Gnomad MID AF: 0.956

Gnomad NFE AF: 0.998

Gnomad OTH AF: 0.920

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

GnomAD4 genome AF: 0.903 AC: 137307 AN: 152068 Hom.: 63622 Cov.: 30 AF XY: 0.906 AC XY: 67352 AN XY: 74338

African (AFR) AF: 0.667 AC: 27625 AN: 41414

American (AMR) AF: 0.962 AC: 14686 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.993 AC: 3446 AN: 3472

East Asian (EAS) AF: 1.00 AC: 5180 AN: 5180

South Asian (SAS) AF: 0.988 AC: 4749 AN: 4808

European-Finnish (FIN) AF: 1.00 AC: 10616 AN: 10616

Middle Eastern (MID) AF: 0.963 AC: 283 AN: 294

European-Non Finnish (NFE) AF: 0.998 AC: 67866 AN: 67990

Other (OTH) AF: 0.921 AC: 1944 AN: 2110

Alfa AF: 0.870 Hom.: 20856

Bravo AF: 0.889

Asia WGS AF: 0.976 AC: 3393 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.55
DANN	Benign	0.33
PhyloP100		-0.95
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: rs2738258; hg19: chr7-99370493;