chr7-99784143-G-T

Variant names:

• chr7-99784143-G-T
• rs12721636
• NM_017460.6:c.-62C>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• 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
• Publications: 5 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=-0.91).
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 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 GnomAdExome4. There are 707 alleles in the male GnomAdExome4 subpopulation. Median coverage is 21. This position passed quality control check.
• BS2: High AC in GnomAd4 at 141 Unknown,AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017460.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP3A4	NM_017460.6	MANE Select	c.-62C>A		5_prime_UTR	Exon 1 of 13	NP_059488.2
	CYP3A4	NM_001202855.3		c.-62C>A		5_prime_UTR	Exon 1 of 13	NP_001189784.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP3A4	ENST00000651514.1	MANE Select	c.-62C>A		5_prime_UTR	Exon 1 of 13	ENSP00000498939.1
	CYP3A4	ENST00000336411.7	TSL:1	c.-62C>A		5_prime_UTR	Exon 1 of 14	ENSP00000337915.3
	CYP3A4	ENST00000652018.1		c.-62C>A		5_prime_UTR	Exon 1 of 11	ENSP00000498733.1

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

African (AFR) AF: 0.000933 AC: 29 AN: 31088

American (AMR) AF: 0.00158 AC: 70 AN: 44272

Ashkenazi Jewish (ASJ) AF: 0.00475 AC: 120 AN: 25258

East Asian (EAS) AF: 0.00 AC: 0 AN: 38836

South Asian (SAS) AF: 0.000970 AC: 81 AN: 83512

European-Finnish (FIN) AF: 0.0000378 AC: 2 AN: 52904

Middle Eastern (MID) AF: 0.0291 AC: 160 AN: 5502

European-Non Finnish (NFE) AF: 0.000773 AC: 775 AN: 1002714

Other (OTH) AF: 0.00240 AC: 135 AN: 56178

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

African (AFR) AF: 0.000265 AC: 11 AN: 41544

American (AMR) AF: 0.00196 AC: 30 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00519 AC: 18 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4818

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10618

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.000853 AC: 58 AN: 68018

Other (OTH) AF: 0.00331 AC: 7 AN: 2114

Alfa AF: 0.00129 Hom.: 0

Bravo AF: 0.00124

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	6.3
DANN	Benign	0.43
PhyloP100		0.73
PromoterAI		-0.019	Neutral
Mutation Taster		=300/0	polymorphism

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

Other links and lift over

dbSNP: rs12721636; hg19: chr7-99381766;