rs12721620

Variant names:

• chr7-99760992-G-A
• rs12721620
• NM_017460.6:c.1254-11C>T

Your query was ambiguous. Multiple possible variants found:

• chr7-99760992-G-A
• chr7-99760992-G-T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_017460.6(CYP3A4):​c.1254-11C>T variant causes a 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.076 (1455 hom., cov: 32)
  • Exomes 𝑓: 0.0083 (1352 hom.)
• Consequence: CYP3A4 NM_017460.6 intron
• Scores: Splicing: ADA: 0.00001808
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.666
• Publications: 11 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=-0.97).
• 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 rank	MANE	Protein	UniProt
CYP3A4	NM_017460.6	c.1254-11C>T		intron_variant	Intron 11 of 12	ENST00000651514.1	NP_059488.2
CYP3A4	NM_001202855.3	c.1251-11C>T		intron_variant	Intron 11 of 12		NP_001189784.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP3A4	ENST00000651514.1	c.1254-11C>T		intron_variant	Intron 11 of 12		NM_017460.6	ENSP00000498939.1

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

GnomAD2 exomes AF: 0.0207 AC: 5162 AN: 249052 AF XY: 0.0157

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 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

African (AFR) AF: 0.278 AC: 9254 AN: 33308

American (AMR) AF: 0.0144 AC: 638 AN: 44288

Ashkenazi Jewish (ASJ) AF: 0.000154 AC: 4 AN: 26026

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39650

South Asian (SAS) AF: 0.00749 AC: 641 AN: 85606

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53354

Middle Eastern (MID) AF: 0.0153 AC: 88 AN: 5754

European-Non Finnish (NFE) AF: 0.000425 AC: 472 AN: 1110880

Other (OTH) AF: 0.0177 AC: 1064 AN: 60264

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

African (AFR) AF: 0.262 AC: 10845 AN: 41452

American (AMR) AF: 0.0324 AC: 495 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.000385 AC: 2 AN: 5190

South Asian (SAS) AF: 0.00975 AC: 47 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.000882 AC: 60 AN: 68018

Other (OTH) AF: 0.0582 AC: 123 AN: 2114

Alfa AF: 0.0477 Hom.: 834

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
PhyloP100		0.67
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs12721620; hg19: chr7-99358615;