15-74720644-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BA1

The NM_001319217.2(CYP1A1):c.1384A>G(p.Ile462Val) variant causes a missense change. The variant allele was found at a frequency of 0.0564 in 1,613,998 control chromosomes in the GnomAD database, including 6,819 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I462N) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.063 ( 874 hom., cov: 32)

Exomes 𝑓: 0.056 ( 5945 hom. )

Consequence

CYP1A1
NM_001319217.2 missense

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: 4.13

Publications

642 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: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.016761065).

BP6

Variant 15-74720644-T-C is Benign according to our data. Variant chr15-74720644-T-C is described in ClinVar as Benign. ClinVar VariationId is 3060599.Status of the report is no_assertion_criteria_provided, 0 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.246 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
CYP1A1	NM_001319217.2 link	c.1384A>G	p.Ile462Val	missense_variant	Exon 7 of 7	ENST00000379727.8	NP_001306146.1
CYP1A1	NM_000499.5 link	c.1384A>G	p.Ile462Val	missense_variant	Exon 7 of 7		NP_000490.1
CYP1A1	NM_001319216.2 link	c.1297A>G	p.Ile433Val	missense_variant	Exon 6 of 6		NP_001306145.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP1A1	ENST00000379727.8 link	c.1384A>G	p.Ile462Val	missense_variant	Exon 7 of 7	1	NM_001319217.2	ENSP00000369050.3

Frequencies

GnomAD3 genomes

AF:

0.0634

AC:

9646

AN:

152082

Hom.:

868

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0144

Gnomad AMI

AF:

0.0537

Gnomad AMR

AF:

0.252

Gnomad ASJ

AF:

0.0317

Gnomad EAS

AF:

0.242

Gnomad SAS

AF:

0.118

Gnomad FIN

AF:

0.0597

Gnomad MID

AF:

0.0633

Gnomad NFE

AF:

0.0355

Gnomad OTH

AF:

0.0761

GnomAD2 exomes

AF:

0.108

AC:

27169

AN:

251354

AF XY:

0.101

show subpopulations

Gnomad AFR exome

AF:

0.0129

Gnomad AMR exome

AF:

0.374

Gnomad ASJ exome

AF:

0.0332

Gnomad EAS exome

AF:

0.246

Gnomad FIN exome

AF:

0.0562

Gnomad NFE exome

AF:

0.0333

Gnomad OTH exome

AF:

0.0892

GnomAD4 exome

AF:

0.0556

AC:

81313

AN:

1461798

Hom.:

5945

Cov.:

AF XY:

0.0565

AC XY:

41084

AN XY:

727208

show subpopulations

African (AFR)

AF:

0.00962

AC:

322

AN:

33478

American (AMR)

AF:

0.363

AC:

16217

AN:

44686

Ashkenazi Jewish (ASJ)

AF:

0.0341

AC:

890

AN:

26132

East Asian (EAS)

AF:

0.234

AC:

9295

AN:

39692

South Asian (SAS)

AF:

0.116

AC:

10014

AN:

86244

European-Finnish (FIN)

AF:

0.0499

AC:

2663

AN:

53414

Middle Eastern (MID)

AF:

0.0534

AC:

308

AN:

5766

European-Non Finnish (NFE)

AF:

0.0341

AC:

37961

AN:

1111994

Other (OTH)

AF:

0.0603

AC:

3643

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

4243

8486

12728

16971

21214

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1740

3480

5220

6960

8700

<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:

0.0634

AC:

9657

AN:

152200

Hom.:

874

Cov.:

AF XY:

0.0697

AC XY:

5185

AN XY:

74412

show subpopulations

African (AFR)

AF:

0.0144

AC:

597

AN:

41554

American (AMR)

AF:

0.252

AC:

3857

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.0317

AC:

110

AN:

3470

East Asian (EAS)

AF:

0.242

AC:

1249

AN:

5158

South Asian (SAS)

AF:

0.119

AC:

574

AN:

4830

European-Finnish (FIN)

AF:

0.0597

AC:

633

AN:

10604

Middle Eastern (MID)

AF:

0.0646

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0355

AC:

2411

AN:

67982

Other (OTH)

AF:

0.0749

AC:

158

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

413

826

1240

1653

2066

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

104

208

312

416

520

<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:

0.0442

Hom.:

1040

Bravo

AF:

0.0768

TwinsUK

AF:

0.0326

AC:

121

ALSPAC

AF:

0.0345

AC:

133

ESP6500AA

AF:

0.0123

AC:

ESP6500EA

AF:

0.0348

AC:

299

ExAC

AF:

0.0940

AC:

11414

Asia WGS

AF:

0.164

AC:

568

AN:

3478

EpiCase

AF:

0.0352

EpiControl

AF:

0.0346

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

CYP1A1-related disorder

Benign:1

Oct 18, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.38

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0072

T;T;T;T;T;T

Eigen

Benign

0.11

Eigen_PC

Benign

0.20

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.80

T;D;T;.;.;.

MetaRNN

Benign

0.017

T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.1

.;.;M;M;M;.

PhyloP100

4.1

PrimateAI

Benign

0.38

PROVEAN

Benign

-0.35

.;.;N;N;N;N

REVEL

Benign

0.18

Sift

Benign

0.27

.;.;T;T;T;T

Sift4G

Benign

0.24

T;T;T;T;T;T

Polyphen

0.14, 0.086

.;B;B;B;B;B

Vest4

0.20

MPC

0.085

ClinPred

0.024

GERP RS

4.5

Varity_R

0.40

gMVP

0.43

Mutation Taster

=92/8

polymorphism (auto)

(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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over