rs4986908

Positions:

• chr7-99769769-C-G
• chr7-99769769-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_017460.6(CYP3A4):​c.520G>C​(p.Asp174His) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00383 in 1,613,948 control chromosomes in the GnomAD database, including 27 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. 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.

• Frequency:
  • Genomes: 𝑓 0.0024 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0040 (26 hom.)
• Consequence: CYP3A4 NM_017460.6 missense, splice_region
• Scores: Splicing: ADA: 0.00004696
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.05

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.013969451).
• BP6: Variant 7-99769769-C-G is Benign according to our data. Variant chr7-99769769-C-G is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd4 at 361 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYP3A4	NM_017460.6	c.520G>C	p.Asp174His	missense_variant, splice_region_variant	6/13	ENST00000651514.1	NP_059488.2
CYP3A4	NM_001202855.3	c.520G>C	p.Asp174His	missense_variant, splice_region_variant	6/13		NP_001189784.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYP3A4	ENST00000651514.1	c.520G>C	p.Asp174His	missense_variant, splice_region_variant	6/13		NM_017460.6	ENSP00000498939.1

Frequencies

GnomAD3 genomes AF: 0.00237 AC: 361 AN: 152190 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00145

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.000659

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00398

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00195 AC: 490 AN: 251268 Hom.: 2 AF XY: 0.00201 AC XY: 273 AN XY: 135790

Gnomad AFR exome AF: 0.00123

Gnomad AMR exome AF: 0.000752

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00140

Gnomad FIN exome AF: 0.000462

Gnomad NFE exome AF: 0.00323

Gnomad OTH exome AF: 0.00359

GnomAD4 exome AF: 0.00398 AC: 5818 AN: 1461640 Hom.: 26 Cov.: 31 AF XY: 0.00379 AC XY: 2759 AN XY: 727126

Gnomad4 AFR exome AF: 0.00129

Gnomad4 AMR exome AF: 0.000895

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00136

Gnomad4 FIN exome AF: 0.000487

Gnomad4 NFE exome AF: 0.00483

Gnomad4 OTH exome AF: 0.00354

GnomAD4 genome AF: 0.00237 AC: 361 AN: 152308 Hom.: 1 Cov.: 32 AF XY: 0.00193 AC XY: 144 AN XY: 74486

Gnomad4 AFR AF: 0.00144

Gnomad4 AMR AF: 0.000915

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000829

Gnomad4 FIN AF: 0.000659

Gnomad4 NFE AF: 0.00398

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000667 Hom.: 0

Bravo AF: 0.00221

TwinsUK AF: 0.00458 AC: 17

ALSPAC AF: 0.00363 AC: 14

ESP6500AA AF: 0.00227 AC: 10

ESP6500EA AF: 0.00360 AC: 31

ExAC AF: 0.00172 AC: 209

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00398

EpiControl AF: 0.00439

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	17
DANN	Benign	0.93
DEOGEN2	Uncertain	0.48	T
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.22
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.43	T
M_CAP	Benign	0.025	T
MetaRNN	Benign	0.014	T
MetaSVM	Benign	-0.66	T
MutationAssessor	Pathogenic	3.4	M
PrimateAI	Benign	0.42	T
PROVEAN	Uncertain	-3.8	D
REVEL	Benign	0.15
Sift	Benign	0.079	T
Sift4G	Uncertain	0.043	D
Polyphen		0.0080	B
Vest4		0.33
MVP		0.81
MPC		0.11
ClinPred		0.076	T
GERP RS		2.8
Varity_R		0.33

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000047
dbscSNV1_RF	Benign	0.0020
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

Publications

LitVar

Other links and lift over

dbSNP: rs4986908; hg19: chr7-99367392; COSMIC: COSV100316085; COSMIC: COSV100316085;