rs4986910

Positions:

• chr7-99760901-A-G

Variant summary

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

The NM_017460.6(CYP3A4):​c.1334T>C​(p.Met445Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00623 in 1,613,728 control chromosomes in the GnomAD database, including 47 homozygotes. In-silico tool predicts 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.

• Frequency:
  • Genomes: 𝑓 0.0050 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0064 (42 hom.)
• Consequence: CYP3A4 NM_017460.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.75

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.021494597).
• BP6: Variant 7-99760901-A-G is Benign according to our data. Variant chr7-99760901-A-G is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd4 at 755 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYP3A4	NM_017460.6	c.1334T>C	p.Met445Thr	missense_variant	12/13	ENST00000651514.1	NP_059488.2
CYP3A4	NM_001202855.3	c.1331T>C	p.Met444Thr	missense_variant	12/13		NP_001189784.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYP3A4	ENST00000651514.1	c.1334T>C	p.Met445Thr	missense_variant	12/13		NM_017460.6	ENSP00000498939	P1

Frequencies

GnomAD3 genomes AF: 0.00496 AC: 755 AN: 152214 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.00104

Gnomad AMI AF: 0.0154

Gnomad AMR AF: 0.00177

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0206

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00653

Gnomad OTH AF: 0.00382

GnomAD3 exomes AF: 0.00524 AC: 1317 AN: 251364 Hom.: 8 AF XY: 0.00509 AC XY: 691 AN XY: 135842

Gnomad AFR exome AF: 0.000861

Gnomad AMR exome AF: 0.00156

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.0180

Gnomad NFE exome AF: 0.00730

Gnomad OTH exome AF: 0.00457

GnomAD4 exome AF: 0.00636 AC: 9296 AN: 1461396 Hom.: 42 Cov.: 31 AF XY: 0.00606 AC XY: 4404 AN XY: 727004

Gnomad4 AFR exome AF: 0.00111

Gnomad4 AMR exome AF: 0.00188

Gnomad4 ASJ exome AF: 0.000115

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000928

Gnomad4 FIN exome AF: 0.0168

Gnomad4 NFE exome AF: 0.00717

Gnomad4 OTH exome AF: 0.00467

GnomAD4 genome AF: 0.00496 AC: 755 AN: 152332 Hom.: 5 Cov.: 32 AF XY: 0.00537 AC XY: 400 AN XY: 74500

Gnomad4 AFR AF: 0.00103

Gnomad4 AMR AF: 0.00176

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0206

Gnomad4 NFE AF: 0.00653

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.00662 Hom.: 3

Bravo AF: 0.00396

TwinsUK AF: 0.00809 AC: 30

ALSPAC AF: 0.00493 AC: 19

ESP6500AA AF: 0.00250 AC: 11

ESP6500EA AF: 0.00779 AC: 67

ExAC AF: 0.00559 AC: 679

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00682

EpiControl AF: 0.00711

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.66
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Uncertain	0.070
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.088	T;T
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.83	T;T
MetaRNN	Benign	0.021	T;T
MetaSVM	Uncertain	0.044	D
MutationAssessor	Pathogenic	3.1	.;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.60	T
PROVEAN	Pathogenic	-5.3	D;D
REVEL	Uncertain	0.47
Sift	Uncertain	0.017	D;D
Sift4G	Uncertain	0.0030	D;D
Polyphen		0.61	P;D
Vest4		0.51
MVP		0.89
MPC		0.14
ClinPred		0.10	T
GERP RS		4.5
Varity_R		0.88

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

Publications

LitVar

Other links and lift over

dbSNP: rs4986910; hg19: chr7-99358524; COSMIC: COSV99080073;