15-74720710-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_001319217.2(CYP1A1):c.1318G>A(p.Asp440Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00527 in 1,614,098 control chromosomes in the GnomAD database, including 27 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D440V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0038 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0054 ( 27 hom. )

Consequence

CYP1A1
NM_001319217.2 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 1.03

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: Benign. The variant received -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.006428659).

BP6

Variant 15-74720710-C-T is Benign according to our data. Variant chr15-74720710-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 777698.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAdExome4 at 27 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001319217.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CYP1A1	NM_001319217.2	MANE Select	c.1318G>A	p.Asp440Asn	missense	Exon 7 of 7	NP_001306146.1	P04798-1
CYP1A1	NM_000499.5		c.1318G>A	p.Asp440Asn	missense	Exon 7 of 7	NP_000490.1	A0N0X8
CYP1A1	NM_001319216.2		c.1231G>A	p.Asp411Asn	missense	Exon 6 of 6	NP_001306145.1	E7EMT5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CYP1A1	ENST00000379727.8	TSL:1 MANE Select	c.1318G>A	p.Asp440Asn	missense	Exon 7 of 7	ENSP00000369050.3	P04798-1
CYP1A1	ENST00000395048.6	TSL:1	c.1318G>A	p.Asp440Asn	missense	Exon 7 of 7	ENSP00000378488.2	P04798-1
CYP1A1	ENST00000567032.5	TSL:1	c.1318G>A	p.Asp440Asn	missense	Exon 7 of 7	ENSP00000456585.1	P04798-1

Frequencies

GnomAD3 genomes

AF:

0.00383

AC:

583

AN:

152128

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000966

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00354

Gnomad ASJ

AF:

0.00461

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00414

Gnomad FIN

AF:

0.00424

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00591

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.00384

AC:

966

AN:

251382

AF XY:

0.00352

show subpopulations

Gnomad AFR exome

AF:

0.000923

Gnomad AMR exome

AF:

0.00231

Gnomad ASJ exome

AF:

0.00308

Gnomad EAS exome

AF:

0.000272

Gnomad FIN exome

AF:

0.00522

Gnomad NFE exome

AF:

0.00565

Gnomad OTH exome

AF:

0.00407

GnomAD4 exome

AF:

0.00542

AC:

7924

AN:

1461852

Hom.:

Cov.:

AF XY:

0.00521

AC XY:

3788

AN XY:

727228

show subpopulations

African (AFR)

AF:

0.000866

AC:

AN:

33480

American (AMR)

AF:

0.00295

AC:

132

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00230

AC:

AN:

26134

East Asian (EAS)

AF:

0.000101

AC:

AN:

39700

South Asian (SAS)

AF:

0.00256

AC:

221

AN:

86256

European-Finnish (FIN)

AF:

0.00575

AC:

307

AN:

53410

Middle Eastern (MID)

AF:

0.00191

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00619

AC:

6878

AN:

1111996

Other (OTH)

AF:

0.00467

AC:

282

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

463

926

1389

1852

2315

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

256

512

768

1024

1280

<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:

0.00383

AC:

583

AN:

152246

Hom.:

Cov.:

AF XY:

0.00387

AC XY:

288

AN XY:

74444

show subpopulations

African (AFR)

AF:

0.000963

AC:

AN:

41530

American (AMR)

AF:

0.00353

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00461

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5176

South Asian (SAS)

AF:

0.00414

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00424

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00591

AC:

402

AN:

68020

Other (OTH)

AF:

0.00237

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

125

156

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.00463

Hom.:

Bravo

AF:

0.00361

TwinsUK

AF:

0.00782

AC:

ALSPAC

AF:

0.00701

AC:

ESP6500AA

AF:

0.000228

AC:

ESP6500EA

AF:

0.00663

AC:

ExAC

AF:

0.00399

AC:

484

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00458

EpiControl

AF:

0.00397

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

CYP1A1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.079

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.63

CADD

Benign

0.11

(source)

DANN

Benign

0.31

DEOGEN2

Benign

0.0056

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.042

LIST_S2

Benign

0.14

M_CAP

Benign

0.014

MetaRNN

Benign

0.0064

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.62

PhyloP100

1.0

PrimateAI

Benign

0.29

PROVEAN

Benign

2.4

REVEL

Benign

0.20

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0010

Vest4

0.070

MVP

0.53

MPC

0.030

ClinPred

0.0022

GERP RS

-2.2

Varity_R

0.21

gMVP

0.43

Mutation Taster

=92/8

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over