rs3735451

Variant names:

• chr7-99758352-T-C
• rs3735451
• NM_017460.6:c.1417-124A>G

Your query was ambiguous. Multiple possible variants found:

• chr7-99758352-T-C
• chr7-99758352-T-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_017460.6(CYP3A4):​c.1417-124A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.17 in 1,177,246 control chromosomes in the GnomAD database, including 31,124 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 0.30 (12103 hom., cov: 32)
  • Exomes 𝑓: 0.15 (19021 hom.)
• Consequence: CYP3A4 NM_017460.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.56

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=-0.98).
• BP6: Variant 7-99758352-T-C is Benign according to our data. Variant chr7-99758352-T-C is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.698 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP3A4	NM_017460.6	c.1417-124A>G		intron_variant	Intron 12 of 12	ENST00000651514.1	NP_059488.2
CYP3A4	NM_001202855.3	c.1414-124A>G		intron_variant	Intron 12 of 12		NP_001189784.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP3A4	ENST00000651514.1	c.1417-124A>G		intron_variant	Intron 12 of 12		NM_017460.6	ENSP00000498939.1

Frequencies

GnomAD3 genomes AF: 0.302 AC: 45859 AN: 151748 Hom.: 12064 Cov.: 32

Gnomad AFR AF: 0.704

Gnomad AMI AF: 0.0716

Gnomad AMR AF: 0.259

Gnomad ASJ AF: 0.116

Gnomad EAS AF: 0.299

Gnomad SAS AF: 0.351

Gnomad FIN AF: 0.109

Gnomad MID AF: 0.228

Gnomad NFE AF: 0.108

Gnomad OTH AF: 0.276

GnomAD4 exome AF: 0.151 AC: 154647 AN: 1025380 Hom.: 19021 AF XY: 0.155 AC XY: 80956 AN XY: 523298

Gnomad4 AFR exome AF: 0.721

Gnomad4 AMR exome AF: 0.274

Gnomad4 ASJ exome AF: 0.116

Gnomad4 EAS exome AF: 0.277

Gnomad4 SAS exome AF: 0.326

Gnomad4 FIN exome AF: 0.115

Gnomad4 NFE exome AF: 0.104

Gnomad4 OTH exome AF: 0.182

GnomAD4 genome AF: 0.303 AC: 45958 AN: 151866 Hom.: 12103 Cov.: 32 AF XY: 0.303 AC XY: 22467 AN XY: 74244

Gnomad4 AFR AF: 0.705

Gnomad4 AMR AF: 0.259

Gnomad4 ASJ AF: 0.116

Gnomad4 EAS AF: 0.299

Gnomad4 SAS AF: 0.351

Gnomad4 FIN AF: 0.109

Gnomad4 NFE AF: 0.108

Gnomad4 OTH AF: 0.277

Alfa AF: 0.135 Hom.: 4008

Bravo AF: 0.328

Asia WGS AF: 0.373 AC: 1296 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	0.67
DANN	Benign	0.39

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: rs3735451; hg19: chr7-99355975;