chr7-99760836-G-A

Variant names:

• chr7-99760836-G-A
• rs4986913
• NM_017460.6:c.1399C>T

Variant summary

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

The NM_017460.6(CYP3A4):​c.1399C>T​(p.Pro467Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000725 in 1,613,960 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000073 (1 hom.)
• Consequence: CYP3A4 NM_017460.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.394
• Publications: 32 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 (MetaRNN=0.0331603).
• BS2: High AC in GnomAd4 at 11 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.1399C>T	p.Pro467Ser	missense	Exon 12 of 13	NP_059488.2
	CYP3A4	NM_001202855.3		c.1396C>T	p.Pro466Ser	missense	Exon 12 of 13	NP_001189784.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP3A4	ENST00000651514.1	MANE Select	c.1399C>T	p.Pro467Ser	missense	Exon 12 of 13	ENSP00000498939.1
	CYP3A4	ENST00000336411.7	TSL:1	c.1492C>T	p.Pro498Ser	missense	Exon 13 of 14	ENSP00000337915.3
	CYP3A4	ENST00000652018.1		c.1252C>T	p.Pro418Ser	missense	Exon 10 of 11	ENSP00000498733.1

Frequencies

GnomAD3 genomes AF: 0.0000723 AC: 11 AN: 152156 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: 0.00228

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000131 AC: 33 AN: 251302 AF XY: 0.000214

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000725 AC: 106 AN: 1461686 Hom.: 1 Cov.: 31 AF XY: 0.000117 AC XY: 85 AN XY: 727128

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39666

South Asian (SAS) AF: 0.00114 AC: 98 AN: 86218

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5764

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111914

Other (OTH) AF: 0.0000497 AC: 3 AN: 60388

GnomAD4 genome AF: 0.0000722 AC: 11 AN: 152274 Hom.: 0 Cov.: 32 AF XY: 0.000134 AC XY: 10 AN XY: 74464

African (AFR) AF: 0.00 AC: 0 AN: 41558

American (AMR) AF: 0.00 AC: 0 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00228 AC: 11 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68016

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.0249 Hom.: 2347

Bravo AF: 0.0000113

ExAC AF: 0.000107 AC: 13

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	21
DANN	Benign	0.92
DEOGEN2	Benign	0.065	T
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.82
FATHMM_MKL	Benign	0.13	N
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.046	D
MetaRNN	Benign	0.033	T
MetaSVM	Benign	-0.67	T
MutationAssessor	Pathogenic	3.0	M
PhyloP100		0.39
PrimateAI	Benign	0.28	T
PROVEAN	Uncertain	-4.2	D
REVEL	Benign	0.16
Sift	Benign	0.030	D
Sift4G	Benign	0.081	T
Polyphen		0.0060	B
Vest4		0.29
MutPred		0.23		Loss of catalytic residue at P467 (P = 0.0025)
MVP		0.63
MPC		0.15
ClinPred		0.34	T
GERP RS		-0.16
Varity_R		0.69
Mutation Taster		=52/48	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs4986913; hg19: chr7-99358459;