rs28371763

Positions:

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

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 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. Variant has been reported in Lovd as Likely benign (no stars).

• 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

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]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 7-99757185-T-A is Benign according to our data. Variant chr7-99757185-T-A is described in Lovd as [Likely_benign].
• 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 2208 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYP3A4	NM_017460.6	c.*948A>T		3_prime_UTR_variant	13/13	ENST00000651514.1	NP_059488.2
CYP3A4	NM_001202855.3	c.*948A>T		3_prime_UTR_variant	13/13		NP_001189784.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYP3A4	ENST00000651514	c.*948A>T		3_prime_UTR_variant	13/13		NM_017460.6	ENSP00000498939.1
CYP3A4	ENST00000354593	c.*948A>T		3_prime_UTR_variant	8/8	5		ENSP00000346607.2

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

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

Gnomad4 AFR AF: 0.00337

Gnomad4 AMR AF: 0.00947

Gnomad4 ASJ AF: 0.0199

Gnomad4 EAS AF: 0.000579

Gnomad4 SAS AF: 0.0352

Gnomad4 FIN AF: 0.0170

Gnomad4 NFE AF: 0.0209

Gnomad4 OTH AF: 0.0156

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 v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.7
DANN	Benign	0.55

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs28371763; hg19: chr7-99354808;