7-99757365-CA-C

Variant names:

• chr7-99757365-CA-C
• rs28969391
• NM_017460.6:c.*767delT

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

The NM_017460.6(CYP3A4):​c.*767delT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.258 in 152,008 control chromosomes in the GnomAD database, including 7,933 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.26 (7932 hom., cov: 26)
  • Exomes 𝑓: 0.075 (1 hom.)
• Consequence: CYP3A4 NM_017460.6 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.00
• Publications: 3 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 -8 ACMG points.

• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.549 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP3A4	NM_017460.6	c.*767delT		3_prime_UTR_variant	Exon 13 of 13	ENST00000651514.1	NP_059488.2
CYP3A4	NM_001202855.3	c.*767delT		3_prime_UTR_variant	Exon 13 of 13		NP_001189784.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP3A4	ENST00000651514.1	c.*767delT		3_prime_UTR_variant	Exon 13 of 13		NM_017460.6	ENSP00000498939.1
CYP3A4	ENST00000354593.6	c.*767delT		3_prime_UTR_variant	Exon 8 of 8	5		ENSP00000346607.2

Frequencies

GnomAD3 genomes AF: 0.258 AC: 39121 AN: 151850 Hom.: 7917 Cov.: 26

Gnomad AFR AF: 0.556

Gnomad AMI AF: 0.0713

Gnomad AMR AF: 0.234

Gnomad ASJ AF: 0.116

Gnomad EAS AF: 0.297

Gnomad SAS AF: 0.349

Gnomad FIN AF: 0.109

Gnomad MID AF: 0.201

Gnomad NFE AF: 0.106

Gnomad OTH AF: 0.241

GnomAD4 exome AF: 0.0750 AC: 3 AN: 40 Hom.: 1 Cov.: 0 AF XY: 0.115 AC XY: 3 AN XY: 26

African (AFR) AC: 0 AN: 0

American (AMR) AF: 0.00 AC: 0 AN: 2

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.0789 AC: 3 AN: 38

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.258 AC: 39179 AN: 151968 Hom.: 7932 Cov.: 26 AF XY: 0.259 AC XY: 19254 AN XY: 74258

African (AFR) AF: 0.556 AC: 22988 AN: 41382

American (AMR) AF: 0.234 AC: 3571 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.116 AC: 401 AN: 3468

East Asian (EAS) AF: 0.298 AC: 1533 AN: 5152

South Asian (SAS) AF: 0.348 AC: 1675 AN: 4808

European-Finnish (FIN) AF: 0.109 AC: 1150 AN: 10576

Middle Eastern (MID) AF: 0.188 AC: 55 AN: 292

European-Non Finnish (NFE) AF: 0.106 AC: 7229 AN: 67984

Other (OTH) AF: 0.242 AC: 512 AN: 2112

Alfa AF: 0.191 Hom.: 607

Bravo AF: 0.279

Asia WGS AF: 0.357 AC: 1242 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs28969391; hg19: chr7-99354988;