rs4986907

Positions:

• chr7-99769804-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 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. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in Lovd as Likely benign (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R162W) has been classified as Likely benign.

• 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

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]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0037257075).
• BP6: Variant 7-99769804-C-T is Benign according to our data. Variant chr7-99769804-C-T is described in Lovd as [Likely_benign].
• 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1247 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYP3A4	NM_017460.6	c.485G>A	p.Arg162Gln	missense_variant	6/13	ENST00000651514.1	NP_059488.2
CYP3A4	NM_001202855.3	c.485G>A	p.Arg162Gln	missense_variant	6/13		NP_001189784.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYP3A4	ENST00000651514.1	c.485G>A	p.Arg162Gln	missense_variant	6/13		NM_017460.6	ENSP00000498939	P1

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

GnomAD3 exomes AF: 0.00221 AC: 555 AN: 251312 Hom.: 9 AF XY: 0.00172 AC XY: 233 AN XY: 135812

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 SAS exome AF: 0.0000327

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

Gnomad4 AFR exome AF: 0.0273

Gnomad4 AMR exome AF: 0.00237

Gnomad4 ASJ exome AF: 0.000115

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000812

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000263

Gnomad4 OTH exome AF: 0.00209

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

Gnomad4 AFR AF: 0.0275

Gnomad4 AMR AF: 0.00451

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000309

Gnomad4 OTH AF: 0.00474

Alfa AF: 0.00209 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 v4.3

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
MutationTaster	Benign	1.0	N;N
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

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

Publications

LitVar

Other links and lift over

dbSNP: rs4986907; hg19: chr7-99367427; COSMIC: COSV60503157; COSMIC: COSV60503157;