rs12721620

Positions:

• chr7-99760992-G-A

Variant summary

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

The NM_017460.6(CYP3A4):​c.1254-11C>T variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0147 in 1,611,300 control chromosomes in the GnomAD database, including 2,807 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 0.076 (1455 hom., cov: 32)
  • Exomes 𝑓: 0.0083 (1352 hom.)
• Consequence: CYP3A4 NM_017460.6 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00001808
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.666

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=-0.97).
• BP6: Variant 7-99760992-G-A is Benign according to our data. Variant chr7-99760992-G-A is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.258 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYP3A4	NM_017460.6	c.1254-11C>T		splice_polypyrimidine_tract_variant, intron_variant		ENST00000651514.1	NP_059488.2
CYP3A4	NM_001202855.3	c.1251-11C>T		splice_polypyrimidine_tract_variant, intron_variant			NP_001189784.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYP3A4	ENST00000651514.1	c.1254-11C>T		splice_polypyrimidine_tract_variant, intron_variant			NM_017460.6	ENSP00000498939	P1

Frequencies

GnomAD3 genomes AF: 0.0760 AC: 11550 AN: 152052 Hom.: 1452 Cov.: 32

Gnomad AFR AF: 0.262

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0324

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.000384

Gnomad SAS AF: 0.00995

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.000882

Gnomad OTH AF: 0.0578

GnomAD3 exomes AF: 0.0207 AC: 5162 AN: 249052 Hom.: 578 AF XY: 0.0157 AC XY: 2108 AN XY: 134534

Gnomad AFR exome AF: 0.268

Gnomad AMR exome AF: 0.0129

Gnomad ASJ exome AF: 0.000201

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00795

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000647

Gnomad OTH exome AF: 0.00923

GnomAD4 exome AF: 0.00834 AC: 12163 AN: 1459130 Hom.: 1352 Cov.: 31 AF XY: 0.00740 AC XY: 5371 AN XY: 725660

Gnomad4 AFR exome AF: 0.278

Gnomad4 AMR exome AF: 0.0144

Gnomad4 ASJ exome AF: 0.000154

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00749

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000425

Gnomad4 OTH exome AF: 0.0177

GnomAD4 genome AF: 0.0761 AC: 11578 AN: 152170 Hom.: 1455 Cov.: 32 AF XY: 0.0739 AC XY: 5501 AN XY: 74408

Gnomad4 AFR AF: 0.262

Gnomad4 AMR AF: 0.0324

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.000385

Gnomad4 SAS AF: 0.00975

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000882

Gnomad4 OTH AF: 0.0582

Alfa AF: 0.0395 Hom.: 510

Bravo AF: 0.0876

Asia WGS AF: 0.0180 AC: 64 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	8.6
DANN	Benign	0.17

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000018
dbscSNV1_RF	Benign	0.044
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: rs12721620; hg19: chr7-99358615; COSMIC: COSV60501317;