Variant 7-99768360-A-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_017460.6(CYP3A4):c.664T>A(p.Ser222Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,613,602 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S222P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

CYP3A4
NM_017460.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0290

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]

CYP3A4 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.11285362).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYP3A4	NM_017460.6 linkuse as main transcript	c.664T>A	p.Ser222Thr	missense_variant	7/13	ENST00000651514.1	NP_059488.2	P08684Q6GRK0
CYP3A4	NM_001202855.3 linkuse as main transcript	c.664T>A	p.Ser222Thr	missense_variant	7/13		NP_001189784.1	P08684Q6GRK0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
CYP3A4	ENST00000651514.1 linkuse as main transcript	c.664T>A	p.Ser222Thr	missense_variant	7/13		NM_017460.6	ENSP00000498939.1	P08684
CYP3A4	ENST00000336411.7 linkuse as main transcript	c.664T>A	p.Ser222Thr	missense_variant	7/14	1		ENSP00000337915.3	A0A499FJM4
CYP3A4	ENST00000652018.1 linkuse as main transcript	c.517T>A	p.Ser173Thr	missense_variant	5/11			ENSP00000498733.1	A0A494C0W7
CYP3A4	ENST00000354593.6 linkuse as main transcript	c.214T>A	p.Ser72Thr	missense_variant	2/8	5		ENSP00000346607.2	E7EVM8

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461404

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727028

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152198

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74366

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.52

CADD

Benign

8.4

DANN

Benign

0.57

DEOGEN2

Benign

0.017

T;T

Eigen

Benign

-0.71

Eigen_PC

Benign

-0.74

FATHMM_MKL

Benign

0.079

LIST_S2

Benign

0.68

T;T

M_CAP

Benign

0.013

MetaRNN

Benign

0.11

T;T

MetaSVM

Benign

-0.91

MutationAssessor

Benign

1.8

.;L

PrimateAI

Benign

0.27

PROVEAN

Benign

-1.1

N;N

REVEL

Benign

0.075

Sift

Benign

0.35

T;T

Sift4G

Benign

0.52

T;T

Polyphen

0.0010

B;B

Vest4

0.15

MutPred

0.49

.;Gain of helix (P = 0.1736);

MVP

0.63

MPC

0.076

ClinPred

0.12

GERP RS

3.1

Varity_R

0.31

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over