rs28371763

Variant names:

• chr7-99757185-T-A
• rs28371763
• NM_017460.6:c.*948A>T

Your query was ambiguous. Multiple possible variants found:

• chr7-99757185-T-A
• chr7-99757185-T-G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_017460.6(CYP3A4):​c.*948A>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 0.0145 in 152,300 control chromosomes in the GnomAD database, including 26 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 0.014 (26 hom., cov: 32)
  • Failed GnomAD Quality Control
• Consequence: CYP3A4 NM_017460.6 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.545
• Publications: 7 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=-0.89).
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0145 (2208/152300) while in subpopulation SAS AF = 0.0352 (170/4832). AF 95% confidence interval is 0.0309. There are 26 homozygotes in GnomAd4. There are 1099 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 2208 Unknown,AD gene.

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.*948A>T		3_prime_UTR	Exon 13 of 13	NP_059488.2
	CYP3A4	NM_001202855.3		c.*948A>T		3_prime_UTR	Exon 13 of 13	NP_001189784.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP3A4	ENST00000651514.1	MANE Select	c.*948A>T		3_prime_UTR	Exon 13 of 13	ENSP00000498939.1	P08684
	CYP3A4	ENST00000859201.1		c.*948A>T		3_prime_UTR	Exon 14 of 14	ENSP00000529260.1
	CYP3A4	ENST00000859200.1		c.*948A>T		3_prime_UTR	Exon 13 of 13	ENSP00000529259.1

Frequencies

GnomAD3 genomes AF: 0.0145 AC: 2207 AN: 152182 Hom.: 26 Cov.: 32

Gnomad AFR AF: 0.00335

Gnomad AMI AF: 0.0197

Gnomad AMR AF: 0.00949

Gnomad ASJ AF: 0.0199

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.0349

Gnomad FIN AF: 0.0170

Gnomad MID AF: 0.0854

Gnomad NFE AF: 0.0209

Gnomad OTH AF: 0.0158

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AC: 0 AN: 0 Hom.: 0 Cov.: 0 AC XY: 0 AN XY: 0

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

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) AC: 0 AN: 0

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.0145 AC: 2208 AN: 152300 Hom.: 26 Cov.: 32 AF XY: 0.0148 AC XY: 1099 AN XY: 74466

African (AFR) AF: 0.00337 AC: 140 AN: 41564

American (AMR) AF: 0.00947 AC: 145 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0199 AC: 69 AN: 3468

East Asian (EAS) AF: 0.000579 AC: 3 AN: 5178

South Asian (SAS) AF: 0.0352 AC: 170 AN: 4832

European-Finnish (FIN) AF: 0.0170 AC: 181 AN: 10618

Middle Eastern (MID) AF: 0.0884 AC: 26 AN: 294

European-Non Finnish (NFE) AF: 0.0209 AC: 1423 AN: 68014

Other (OTH) AF: 0.0156 AC: 33 AN: 2116

Alfa AF: 0.0167 Hom.: 18

Bravo AF: 0.0139

Asia WGS AF: 0.0140 AC: 48 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.7
DANN	Benign	0.55
PhyloP100		0.55
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: rs28371763; hg19: chr7-99354808;