15-74720638-G-T

Position:

chr15-74720638-G-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.1390C>A(p.Arg464Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00702 in 1,614,134 control chromosomes in the GnomAD database, including 53 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R464C) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0045 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0073 ( 50 hom. )

Consequence

CYP1A1
NM_001319217.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 2.71

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=0.019624025).

BP6

Variant 15-74720638-G-T is Benign according to our data. Variant chr15-74720638-G-T is described in ClinVar as [Benign]. Clinvar id is 717748.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
CYP1A1	NM_001319217.2 linkuse as main transcript	c.1390C>A	p.Arg464Ser	missense_variant	7/7	ENST00000379727.8
CYP1A1	NM_000499.5 linkuse as main transcript	c.1390C>A	p.Arg464Ser	missense_variant	7/7
CYP1A1	NM_001319216.2 linkuse as main transcript	c.1303C>A	p.Arg435Ser	missense_variant	6/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP1A1	ENST00000379727.8 linkuse as main transcript	c.1390C>A	p.Arg464Ser	missense_variant	7/7	1	NM_001319217.2	P1	P04798-1

Frequencies

GnomAD3 genomes

AF:

0.00454

AC:

690

AN:

152148

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00179

Gnomad AMI

AF:

0.0296

Gnomad AMR

AF:

0.000589

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00170

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00813

Gnomad OTH

AF:

0.00287

GnomAD3 exomes

AF:

0.00425

AC:

1069

AN:

251424

Hom.:

AF XY:

0.00425

AC XY:

578

AN XY:

135880

show subpopulations

Gnomad AFR exome

AF:

0.000984

Gnomad AMR exome

AF:

0.000434

Gnomad ASJ exome

AF:

0.000298

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00203

Gnomad NFE exome

AF:

0.00850

Gnomad OTH exome

AF:

0.00375

GnomAD4 exome

AF:

0.00728

AC:

10638

AN:

1461868

Hom.:

Cov.:

AF XY:

0.00702

AC XY:

5104

AN XY:

727236

show subpopulations

Gnomad4 AFR exome

AF:

0.00131

Gnomad4 AMR exome

AF:

0.000626

Gnomad4 ASJ exome

AF:

0.000459

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00296

Gnomad4 NFE exome

AF:

0.00911

Gnomad4 OTH exome

AF:

0.00444

GnomAD4 genome

AF:

0.00453

AC:

690

AN:

152266

Hom.:

Cov.:

AF XY:

0.00403

AC XY:

300

AN XY:

74454

show subpopulations

Gnomad4 AFR

AF:

0.00178

Gnomad4 AMR

AF:

0.000588

Gnomad4 ASJ

AF:

0.000576

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00170

Gnomad4 NFE

AF:

0.00813

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.00657

Hom.:

Bravo

AF:

0.00419

TwinsUK

AF:

0.00782

AC:

ALSPAC

AF:

0.00908

AC:

ESP6500AA

AF:

0.00137

AC:

ESP6500EA

AF:

0.00663

AC:

ExAC

AF:

0.00450

AC:

546

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 07, 2018	- -

CYP1A1-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 10, 2019

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

Pathogenic

0.81

BayesDel_addAF

Benign

-0.032

BayesDel_noAF

Pathogenic

0.19

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.078

T;T;D;D;D;T

Eigen

Pathogenic

0.73

Eigen_PC

Pathogenic

0.69

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.93

D;D;D;.;.;.

M_CAP

Uncertain

0.086

MetaRNN

Benign

0.020

T;T;T;T;T;T

MetaSVM

Uncertain

0.050

MutationAssessor

Pathogenic

3.8

.;.;H;H;H;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Benign

0.36

PROVEAN

Uncertain

-4.2

.;.;D;D;D;D

REVEL

Uncertain

0.52

Sift

Uncertain

0.0010

.;.;D;D;D;D

Sift4G

Pathogenic

0.0010

D;D;D;D;D;D

Polyphen

0.81

.;P;P;P;P;P

Vest4

0.68

MVP

0.95

MPC

0.20

ClinPred

0.10

GERP RS

5.6

Varity_R

0.88

gMVP

0.84

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