chr15-74720710-C-T

Position:

chr15-74720710-C-T

Variant summary

Our verdict is Benign. Variant got -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. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

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

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 made for transcript

Verdict is Benign. Variant got -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 id is 777698.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAdExome4 at 27 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
CYP1A1	NM_001319217.2 linkuse as main transcript	c.1318G>A	p.Asp440Asn	missense_variant	7/7	ENST00000379727.8
CYP1A1	NM_000499.5 linkuse as main transcript	c.1318G>A	p.Asp440Asn	missense_variant	7/7
CYP1A1	NM_001319216.2 linkuse as main transcript	c.1231G>A	p.Asp411Asn	missense_variant	6/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP1A1	ENST00000379727.8 linkuse as main transcript	c.1318G>A	p.Asp440Asn	missense_variant	7/7	1	NM_001319217.2	P1	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

GnomAD3 exomes

AF:

0.00384

AC:

966

AN:

251382

Hom.:

AF XY:

0.00352

AC XY:

478

AN XY:

135860

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 SAS exome

AF:

0.00180

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

Gnomad4 AFR exome

AF:

0.000866

Gnomad4 AMR exome

AF:

0.00295

Gnomad4 ASJ exome

AF:

0.00230

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.00256

Gnomad4 FIN exome

AF:

0.00575

Gnomad4 NFE exome

AF:

0.00619

Gnomad4 OTH exome

AF:

0.00467

GnomAD4 genome

AF:

0.00383

AC:

583

AN:

152246

Hom.:

Cov.:

AF XY:

0.00387

AC XY:

288

AN XY:

74444

show subpopulations

Gnomad4 AFR

AF:

0.000963

Gnomad4 AMR

AF:

0.00353

Gnomad4 ASJ

AF:

0.00461

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00414

Gnomad4 FIN

AF:

0.00424

Gnomad4 NFE

AF:

0.00591

Gnomad4 OTH

AF:

0.00237

Alfa

AF:

0.00485

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

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 13, 2018	- -

CYP1A1-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 30, 2019

This variant is classified as likely 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

0.079

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.63

CADD

Benign

0.11

DANN

Benign

0.31

DEOGEN2

Benign

0.0056

T;T;T;T;T;T

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.042

LIST_S2

Benign

0.14

T;T;T;.;.;.

M_CAP

Benign

0.014

MetaRNN

Benign

0.0064

T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.62

.;.;N;N;N;.

MutationTaster

Benign

0.99

N;N;N;N

PrimateAI

Benign

0.29

PROVEAN

Benign

2.4

.;.;N;N;N;N

REVEL

Benign

0.20

Sift

Benign

1.0

.;.;T;T;T;T

Sift4G

Benign

1.0

T;T;T;T;T;T

Polyphen

0.0010

.;B;B;B;B;B

Vest4

0.070

MVP

0.53

MPC

0.030

ClinPred

0.0022

GERP RS

-2.2

Varity_R

0.21

gMVP

0.43

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

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over