rs4986910

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_017460.6(CYP3A4):ā€‹c.1334T>Cā€‹(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: š‘“ 0.0050 ( 5 hom., cov: 32)
Exomes š‘“: 0.0064 ( 42 hom. )

Consequence

CYP3A4
NM_017460.6 missense

Scores

3
10
5

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.75
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

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
CYP3A4NM_017460.6 linkuse as main transcriptc.1334T>C p.Met445Thr missense_variant 12/13 ENST00000651514.1 NP_059488.2
CYP3A4NM_001202855.3 linkuse as main transcriptc.1331T>C p.Met444Thr missense_variant 12/13 NP_001189784.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CYP3A4ENST00000651514.1 linkuse as main transcriptc.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
show subpopulations
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
show subpopulations
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
show subpopulations
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
show subpopulations
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

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