dbSNP rs2229150: CYP1A1:p.Arg93Trp (chr15-74722821-G-A) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001319217.2(CYP1A1):c.277C>T(p.Arg93Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000783 in 1,614,006 control chromosomes in the GnomAD database, including 3 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R93Q) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00062 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00080 ( 2 hom. )

Consequence

CYP1A1
NM_001319217.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.290

Publications

9 publications found

Variant links:

Genes affected

CYP1A1 (HGNC:2595): (cytochrome P450 family 1 subfamily A member 1) This gene, CYP1A1, encodes a member of the cytochrome P450 superfamily of enzymes. The cytochrome P450 proteins are monooxygenases which 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 some polycyclic aromatic hydrocarbons (PAHs), some of which are found in cigarette smoke. The enzyme's endogenous substrate is unknown; however, it is able to metabolize some PAHs to carcinogenic intermediates. The gene has been associated with lung cancer risk. A related family member, CYP1A2, is located approximately 25 kb away from CYP1A1 on chromosome 15. Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Jan 2016]

CYP1A1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.12483463).

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP1A1	NM_001319217.2 link	c.277C>T	p.Arg93Trp	missense_variant	Exon 2 of 7	ENST00000379727.8	NP_001306146.1	P04798-1A0N0X8
CYP1A1	NM_000499.5 link	c.277C>T	p.Arg93Trp	missense_variant	Exon 2 of 7		NP_000490.1	P04798-1A0N0X8
CYP1A1	NM_001319216.2 link	c.277C>T	p.Arg93Trp	missense_variant	Exon 2 of 6		NP_001306145.1	P04798E7EMT5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP1A1	ENST00000379727.8 link	c.277C>T	p.Arg93Trp	missense_variant	Exon 2 of 7	1	NM_001319217.2	ENSP00000369050.3		P04798-1

Frequencies

GnomAD3 genomes

AF:

0.000624

AC:

AN:

152136

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000266

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00105

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000956

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000685

AC:

172

AN:

251228

AF XY:

0.000729

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.000376

Gnomad ASJ exome

AF:

0.000397

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000139

Gnomad NFE exome

AF:

0.00107

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000799

AC:

1168

AN:

1461752

Hom.:

Cov.:

AF XY:

0.000791

AC XY:

575

AN XY:

727188

show subpopulations

African (AFR)

AF:

0.000149

AC:

AN:

33480

American (AMR)

AF:

0.000402

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.000344

AC:

AN:

26134

East Asian (EAS)

AF:

0.000327

AC:

AN:

39700

South Asian (SAS)

AF:

0.000812

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.0000751

AC:

AN:

53290

Middle Eastern (MID)

AF:

0.00121

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000910

AC:

1012

AN:

1112006

Other (OTH)

AF:

0.000497

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

160

240

320

400

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

114

152

190

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000624

AC:

AN:

152254

Hom.:

Cov.:

AF XY:

0.000618

AC XY:

AN XY:

74440

show subpopulations

African (AFR)

AF:

0.000265

AC:

AN:

41538

American (AMR)

AF:

0.00105

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.000415

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000956

AC:

AN:

68014

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000891

Hom.:

Bravo

AF:

0.000582

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00105

AC:

ExAC

AF:

0.000749

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000818

EpiControl

AF:

0.000652

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.22

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.21

T;T;D;D;D;T

Eigen

Uncertain

0.23

Eigen_PC

Benign

-0.012

FATHMM_MKL

Benign

0.41

LIST_S2

Uncertain

0.93

D;D;D;.;.;.

M_CAP

Benign

0.057

MetaRNN

Benign

0.12

T;T;T;T;T;T

MetaSVM

Uncertain

0.22

MutationAssessor

Pathogenic

4.1

.;.;H;H;H;.

PhyloP100

0.29

PrimateAI

Benign

0.30

PROVEAN

Pathogenic

-5.6

.;.;D;D;D;D

REVEL

Uncertain

0.41

Sift

Pathogenic

0.0

.;.;D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D;D;D

Polyphen

1.0, 1.0

.;D;D;D;D;D

Vest4

0.37

MVP

0.97

MPC

0.034

ClinPred

0.11

GERP RS

-1.1

Varity_R

0.66

gMVP

0.77

Mutation Taster

=55/45

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over