NM_017460.6:c.485G>A

Variant names:

• chr7-99769804-C-T
• rs4986907
• NM_017460.6:c.485G>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.485G>A​(p.Arg162Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00168 in 1,613,964 control chromosomes in the GnomAD database, including 39 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/20 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 0.0082 (22 hom., cov: 32)
  • Exomes 𝑓: 0.0010 (17 hom.)
• Consequence: CYP3A4 NM_017460.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.13
• Publications: 38 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 (MetaRNN=0.0037257075).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00819 (1247/152258) while in subpopulation AFR AF = 0.0275 (1144/41542). AF 95% confidence interval is 0.0262. There are 22 homozygotes in GnomAd4. There are 573 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1247 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.485G>A	p.Arg162Gln	missense	Exon 6 of 13	NP_059488.2
	CYP3A4	NM_001202855.3		c.485G>A	p.Arg162Gln	missense	Exon 6 of 13	NP_001189784.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP3A4	ENST00000651514.1	MANE Select	c.485G>A	p.Arg162Gln	missense	Exon 6 of 13	ENSP00000498939.1	P08684
	CYP3A4	ENST00000336411.7	TSL:1	c.485G>A	p.Arg162Gln	missense	Exon 6 of 14	ENSP00000337915.3	A0A499FJM4
	CYP3A4	ENST00000859201.1		c.485G>A	p.Arg162Gln	missense	Exon 6 of 14	ENSP00000529260.1

Frequencies

GnomAD3 genomes AF: 0.00820 AC: 1247 AN: 152140 Hom.: 22 Cov.: 32

Gnomad AFR AF: 0.0276

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00451

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000309

Gnomad OTH AF: 0.00479

GnomAD2 exomes AF: 0.00221 AC: 555 AN: 251312 AF XY: 0.00172

Gnomad AFR exome AF: 0.0265

Gnomad AMR exome AF: 0.00246

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000220

Gnomad OTH exome AF: 0.00212

GnomAD4 exome AF: 0.00100 AC: 1462 AN: 1461706 Hom.: 17 Cov.: 31 AF XY: 0.000893 AC XY: 649 AN XY: 727164

African (AFR) AF: 0.0273 AC: 915 AN: 33460

American (AMR) AF: 0.00237 AC: 106 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.000115 AC: 3 AN: 26126

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39696

South Asian (SAS) AF: 0.0000812 AC: 7 AN: 86258

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53420

Middle Eastern (MID) AF: 0.00191 AC: 11 AN: 5764

European-Non Finnish (NFE) AF: 0.000263 AC: 292 AN: 1111890

Other (OTH) AF: 0.00209 AC: 126 AN: 60378

GnomAD4 genome AF: 0.00819 AC: 1247 AN: 152258 Hom.: 22 Cov.: 32 AF XY: 0.00770 AC XY: 573 AN XY: 74454

African (AFR) AF: 0.0275 AC: 1144 AN: 41542

American (AMR) AF: 0.00451 AC: 69 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

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

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000309 AC: 21 AN: 68014

Other (OTH) AF: 0.00474 AC: 10 AN: 2110

Alfa AF: 0.00288 Hom.: 4

Bravo AF: 0.00972

ESP6500AA AF: 0.0300 AC: 132

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00243 AC: 295

EpiCase AF: 0.000382

EpiControl AF: 0.000237

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	0.20
DANN	Benign	0.78
DEOGEN2	Benign	0.16	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.0010	N
LIST_S2	Benign	0.15	T
MetaRNN	Benign	0.0037	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.82	N
PhyloP100		1.1
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.22	N
REVEL	Benign	0.081
Sift	Benign	0.36	T
Sift4G	Benign	0.18	T
Polyphen		0.0030	B
Vest4		0.071
MVP		0.43
MPC		0.096
ClinPred		0.0075	T
GERP RS		-2.8
Varity_R		0.043
Mutation Taster		=94/6	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: rs4986907; hg19: chr7-99367427; COSMIC: COSV60503157; COSMIC: COSV60503157;