NM_017460.6:c.1334T>C

Variant names:

• chr7-99760901-A-G
• rs4986910
• NM_017460.6:c.1334T>C

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0050 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0064 (42 hom.)
• Consequence: CYP3A4 NM_017460.6 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 4.75
• Publications: 97 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=0.021494597).
• BS2: High AC in GnomAd4 at 755 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.1334T>C	p.Met445Thr	missense	Exon 12 of 13	NP_059488.2
	CYP3A4	NM_001202855.3		c.1331T>C	p.Met444Thr	missense	Exon 12 of 13	NP_001189784.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP3A4	ENST00000651514.1	MANE Select	c.1334T>C	p.Met445Thr	missense	Exon 12 of 13	ENSP00000498939.1	P08684
	CYP3A4	ENST00000336411.7	TSL:1	c.1427T>C	p.Met476Thr	missense	Exon 13 of 14	ENSP00000337915.3	A0A499FJM4
	CYP3A4	ENST00000859201.1		c.1424T>C	p.Met475Thr	missense	Exon 13 of 14	ENSP00000529260.1

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

GnomAD2 exomes AF: 0.00524 AC: 1317 AN: 251364 AF XY: 0.00509

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 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

African (AFR) AF: 0.00111 AC: 37 AN: 33476

American (AMR) AF: 0.00188 AC: 84 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.000115 AC: 3 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39664

South Asian (SAS) AF: 0.0000928 AC: 8 AN: 86252

European-Finnish (FIN) AF: 0.0168 AC: 899 AN: 53384

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5760

European-Non Finnish (NFE) AF: 0.00717 AC: 7975 AN: 1111634

Other (OTH) AF: 0.00467 AC: 282 AN: 60380

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

African (AFR) AF: 0.00103 AC: 43 AN: 41578

American (AMR) AF: 0.00176 AC: 27 AN: 15306

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.0206 AC: 219 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00653 AC: 444 AN: 68026

Other (OTH) AF: 0.00378 AC: 8 AN: 2114

Alfa AF: 0.00607 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

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.83	T
MetaRNN	Benign	0.021	T
MetaSVM	Uncertain	0.044	D
MutationAssessor	Pathogenic	3.1	M
PhyloP100		4.7
PrimateAI	Uncertain	0.60	T
PROVEAN	Pathogenic	-5.3	D
REVEL	Uncertain	0.47
Sift	Uncertain	0.017	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.61	P
Vest4		0.51
MVP		0.89
MPC		0.14
ClinPred		0.10	T
GERP RS		4.5
Varity_R		0.88
Mutation Taster		=85/15	polymorphism

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

Other links and lift over

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