rs28988604

Variant names:

• chr7-99757450-G-A
• rs28988604
• NM_017460.6:c.*683C>T

Your query was ambiguous. Multiple possible variants found:

• chr7-99757450-G-A
• chr7-99757450-G-C

Variant summary

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

The NM_017460.6(CYP3A4):​c.*683C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0292 in 152,500 control chromosomes in the GnomAD database, including 91 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 0.029 (91 hom., cov: 32)
  • Exomes 𝑓: 0.012 (0 hom.)
• Consequence: CYP3A4 NM_017460.6 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0480
• 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=-1.03).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0527 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP3A4	NM_017460.6	MANE Select	c.*683C>T		3_prime_UTR	Exon 13 of 13	NP_059488.2
	CYP3A4	NM_001202855.3		c.*683C>T		3_prime_UTR	Exon 13 of 13	NP_001189784.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP3A4	ENST00000651514.1	MANE Select	c.*683C>T		3_prime_UTR	Exon 13 of 13	ENSP00000498939.1
	CYP3A4	ENST00000354593.6	TSL:5	c.*683C>T		3_prime_UTR	Exon 8 of 8	ENSP00000346607.2
	CYP3A4	ENST00000336411.7	TSL:1	c.*683C>T		downstream_gene	N/A	ENSP00000337915.3

Frequencies

GnomAD3 genomes AF: 0.0292 AC: 4435 AN: 152124 Hom.: 90 Cov.: 32

Gnomad AFR AF: 0.0546

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0323

Gnomad ASJ AF: 0.0132

Gnomad EAS AF: 0.00135

Gnomad SAS AF: 0.00644

Gnomad FIN AF: 0.0406

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0161

Gnomad OTH AF: 0.0302

GnomAD4 exome AF: 0.0116 AC: 3 AN: 258 Hom.: 0 Cov.: 0 AF XY: 0.0120 AC XY: 2 AN XY: 166

African (AFR) AF: 0.00 AC: 0 AN: 4

American (AMR) AF: 0.00 AC: 0 AN: 12

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 4

East Asian (EAS) AF: 0.00 AC: 0 AN: 8

South Asian (SAS) AF: 0.00 AC: 0 AN: 2

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.0135 AC: 3 AN: 222

Other (OTH) AF: 0.00 AC: 0 AN: 4

GnomAD4 genome AF: 0.0292 AC: 4449 AN: 152242 Hom.: 91 Cov.: 32 AF XY: 0.0297 AC XY: 2208 AN XY: 74430

African (AFR) AF: 0.0546 AC: 2267 AN: 41542

American (AMR) AF: 0.0323 AC: 495 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0132 AC: 46 AN: 3472

East Asian (EAS) AF: 0.00135 AC: 7 AN: 5180

South Asian (SAS) AF: 0.00644 AC: 31 AN: 4812

European-Finnish (FIN) AF: 0.0406 AC: 430 AN: 10600

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.0161 AC: 1095 AN: 68020

Other (OTH) AF: 0.0327 AC: 69 AN: 2108

Alfa AF: 0.00986 Hom.: 1

Bravo AF: 0.0310

Asia WGS AF: 0.0120 AC: 41 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	1.4
DANN	Benign	0.41
PhyloP100		-0.048
Mutation Taster		=100/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs28988604; hg19: chr7-99355073;