rs55785340

Variant summary

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

The NM_017460.6(CYP3A4):c.664T>C(p.Ser222Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000431 in 1,613,720 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict 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 0.00060 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00041 ( 6 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:

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=0.007305056).

BP6

Variant 7-99768360-A-G is Benign according to our data. Variant chr7-99768360-A-G is described in Lovd as [Likely_benign].

BS2

High AC in GnomAd at 91 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYP3A4	NM_017460.6 linkuse as main transcript	c.664T>C	p.Ser222Pro	missense_variant	7/13	ENST00000651514.1
CYP3A4	NM_001202855.3 linkuse as main transcript	c.664T>C	p.Ser222Pro	missense_variant	7/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
CYP3A4	ENST00000651514.1 linkuse as main transcript	c.664T>C	p.Ser222Pro	missense_variant	7/13		NM_017460.6	P1
CYP3A4	ENST00000336411.7 linkuse as main transcript	c.664T>C	p.Ser222Pro	missense_variant	7/14	1
CYP3A4	ENST00000652018.1 linkuse as main transcript	c.517T>C	p.Ser173Pro	missense_variant	5/11
CYP3A4	ENST00000354593.6 linkuse as main transcript	c.214T>C	p.Ser72Pro	missense_variant	2/8	5

Frequencies

GnomAD3 genomes

AF:

0.000598

AC:

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.00724

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000191

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000956

AC:

240

AN:

251054

Hom.:

AF XY:

0.000855

AC XY:

116

AN XY:

135682

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00999

Gnomad NFE exome

AF:

0.000141

Gnomad OTH exome

AF:

0.00131

GnomAD4 exome

AF:

0.000414

AC:

605

AN:

1461404

Hom.:

Cov.:

AF XY:

0.000424

AC XY:

308

AN XY:

727028

show subpopulations

Gnomad4 AFR exome

AF:

0.00

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:

0.0100

Gnomad4 NFE exome

AF:

0.0000342

Gnomad4 OTH exome

AF:

0.000513

GnomAD4 genome

AF:

0.000597

AC:

AN:

152316

Hom.:

Cov.:

AF XY:

0.000792

AC XY:

AN XY:

74494

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00724

Gnomad4 NFE

AF:

0.000191

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000651

Hom.:

Bravo

AF:

0.0000264

ExAC

AF:

0.000865

AC:

105

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.33

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.36

Cadd

Benign

Dann

Benign

0.95

DEOGEN2

Benign

0.080

T;T

Eigen

Benign

-0.48

Eigen_PC

Benign

-0.58

FATHMM_MKL

Benign

0.080

LIST_S2

Uncertain

0.89

D;D

MetaRNN

Benign

0.0073

T;T

MetaSVM

Benign

-0.58

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.28

PROVEAN

Uncertain

-2.8

D;D

REVEL

Benign

0.14

Sift

Benign

0.099

T;T

Sift4G

Benign

0.26

T;T

Polyphen

0.74

P;B

Vest4

0.38

MVP

0.72

MPC

0.11

ClinPred

0.16

GERP RS

3.1

Varity_R

0.85

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