rs12721636

Positions:

• chr7-99784143-G-T

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.-62C>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00101 in 1,492,528 control chromosomes in the GnomAD database, including 14 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 0.00093 (1 hom., cov: 31)
  • Exomes 𝑓: 0.0010 (13 hom.)
• Consequence: CYP3A4 NM_017460.6 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.728

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=-0.91).
• BP6: Variant 7-99784143-G-T is Benign according to our data. Variant chr7-99784143-G-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00102 (1372/1340264) while in subpopulation MID AF= 0.0291 (160/5502). AF 95% confidence interval is 0.0254. There are 13 homozygotes in gnomad4_exome. There are 707 alleles in male gnomad4_exome subpopulation. Median coverage is 21. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 141 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYP3A4	NM_017460.6	c.-62C>A		5_prime_UTR_variant	1/13	ENST00000651514.1	NP_059488.2
CYP3A4	NM_001202855.3	c.-62C>A		5_prime_UTR_variant	1/13		NP_001189784.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYP3A4	ENST00000651514.1	c.-62C>A		5_prime_UTR_variant	1/13		NM_017460.6	ENSP00000498939	P1

Frequencies

GnomAD3 genomes AF: 0.000920 AC: 140 AN: 152146 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00196

Gnomad ASJ AF: 0.00519

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.000853

Gnomad OTH AF: 0.00335

GnomAD4 exome AF: 0.00102 AC: 1372 AN: 1340264 Hom.: 13 Cov.: 21 AF XY: 0.00105 AC XY: 707 AN XY: 673610

Gnomad4 AFR exome AF: 0.000933

Gnomad4 AMR exome AF: 0.00158

Gnomad4 ASJ exome AF: 0.00475

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000970

Gnomad4 FIN exome AF: 0.0000378

Gnomad4 NFE exome AF: 0.000773

Gnomad4 OTH exome AF: 0.00240

GnomAD4 genome AF: 0.000926 AC: 141 AN: 152264 Hom.: 1 Cov.: 31 AF XY: 0.000913 AC XY: 68 AN XY: 74468

Gnomad4 AFR AF: 0.000265

Gnomad4 AMR AF: 0.00196

Gnomad4 ASJ AF: 0.00519

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.000853

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00146 Hom.: 0

Bravo AF: 0.00124

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	6.3
DANN	Benign	0.43

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

Publications

LitVar

Other links and lift over

dbSNP: rs12721636; hg19: chr7-99381766;