chr7-99758352-T-G

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_017460.6(CYP3A4):​c.1417-124A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000263 in 1,178,462 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000029 (0 hom.)
• Consequence: CYP3A4 NM_017460.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.56
• Publications: 42 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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BS2: High AC in GnomAdExome4 at 30 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP3A4	NM_017460.6	MANE Select	c.1417-124A>C		intron	N/A	NP_059488.2
	CYP3A4	NM_001202855.3		c.1414-124A>C		intron	N/A	NP_001189784.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP3A4	ENST00000651514.1	MANE Select	c.1417-124A>C		intron	N/A	ENSP00000498939.1	P08684
	CYP3A4	ENST00000336411.7	TSL:1	c.1510-124A>C		intron	N/A	ENSP00000337915.3	A0A499FJM4
	CYP3A4	ENST00000859201.1		c.1507-124A>C		intron	N/A	ENSP00000529260.1

Frequencies

GnomAD3 genomes AF: 0.00000659 AC: 1 AN: 151800 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000292 AC: 30 AN: 1026662 Hom.: 0 AF XY: 0.0000286 AC XY: 15 AN XY: 523944

African (AFR) AF: 0.00 AC: 0 AN: 24464

American (AMR) AF: 0.00 AC: 0 AN: 36348

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22384

East Asian (EAS) AF: 0.00 AC: 0 AN: 36194

South Asian (SAS) AF: 0.0000136 AC: 1 AN: 73428

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 41996

Middle Eastern (MID) AF: 0.000306 AC: 1 AN: 3270

European-Non Finnish (NFE) AF: 0.0000363 AC: 27 AN: 743054

Other (OTH) AF: 0.0000220 AC: 1 AN: 45524

GnomAD4 genome AF: 0.00000659 AC: 1 AN: 151800 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74146

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41340

American (AMR) AF: 0.00 AC: 0 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 5144

South Asian (SAS) AF: 0.00 AC: 0 AN: 4802

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10582

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67898

Other (OTH) AF: 0.00 AC: 0 AN: 2094

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 17039

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.59
DANN	Benign	0.33
PhyloP100		-1.6

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: rs3735451; hg19: chr7-99355975;