7-99768470-G-C
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP5BP4BS2
The NM_017460.6(CYP3A4):c.554C>G(p.Thr185Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000274 in 1,614,024 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in Lovd as Pathogenic (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.
Frequency
Genomes: 𝑓 0.00011 ( 0 hom., cov: 31)
Exomes 𝑓: 0.00029 ( 9 hom. )
Consequence
CYP3A4
NM_017460.6 missense
NM_017460.6 missense
Scores
7
11
Clinical Significance
Not reported in ClinVar
Conservation
PhyloP100: 5.31
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -4 ACMG points.
PP5
?
Variant 7-99768470-G-C is Pathogenic according to our data. Variant chr7-99768470-G-C is described in Lovd as [Pathogenic].
BP4
?
Computational evidence support a benign effect (MetaRNN=0.03089279).. Strength limited to SUPPORTING due to the PP5.
BS2
?
High AC in GnomAd at 17 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CYP3A4 | NM_017460.6 | c.554C>G | p.Thr185Ser | missense_variant | 7/13 | ENST00000651514.1 | |
CYP3A4 | NM_001202855.3 | c.554C>G | p.Thr185Ser | missense_variant | 7/13 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CYP3A4 | ENST00000651514.1 | c.554C>G | p.Thr185Ser | missense_variant | 7/13 | NM_017460.6 | P1 | ||
CYP3A4 | ENST00000336411.7 | c.554C>G | p.Thr185Ser | missense_variant | 7/14 | 1 | |||
CYP3A4 | ENST00000652018.1 | c.407C>G | p.Thr136Ser | missense_variant | 5/11 | ||||
CYP3A4 | ENST00000354593.6 | c.104C>G | p.Thr35Ser | missense_variant | 2/8 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.000112 AC: 17AN: 152196Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.0000756 AC: 19AN: 251308Hom.: 0 AF XY: 0.0000515 AC XY: 7AN XY: 135810
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GnomAD4 exome AF: 0.000291 AC: 425AN: 1461710Hom.: 9 Cov.: 32 AF XY: 0.000253 AC XY: 184AN XY: 727162
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ClinVar
Not reported inComputational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
Cadd
Uncertain
Dann
Uncertain
DEOGEN2
Benign
T;T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D
M_CAP
Benign
T
MetaRNN
Benign
T;T
MetaSVM
Benign
T
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D
REVEL
Benign
Sift
Benign
T;T
Sift4G
Benign
T;T
Polyphen
P;B
Vest4
MutPred
0.28
.;Gain of disorder (P = 0.1795);
MVP
MPC
0.32
ClinPred
T
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Varity_R
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at