15-74720638-G-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.71

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]

ACMG classification

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 GnomAd at 3 AR gene

Transcripts

RefSeq

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

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.00454 AC: 690 AN: 152148 Hom.: 3 Cov.: 32

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.: 3 AF XY: 0.00425 AC XY: 578 AN XY: 135880

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.: 50 Cov.: 31 AF XY: 0.00702 AC XY: 5104 AN XY: 727236

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.: 3 Cov.: 32 AF XY: 0.00403 AC XY: 300 AN XY: 74454

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.: 15

Bravo AF: 0.00419

TwinsUK AF: 0.00782 AC: 29

ALSPAC AF: 0.00908 AC: 35

ESP6500AA AF: 0.00137 AC: 6

ESP6500EA AF: 0.00663 AC: 57

ExAC AF: 0.00450 AC: 546

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Aug 07, 2018

- -

CYP1A1-related disorder Benign:1

Benign, criteria provided, single submitter

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	T
BayesDel_noAF	Pathogenic	0.19
Cadd	Uncertain	24
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	D
LIST_S2	Uncertain	0.93	D;D;D;.;.;.
M_CAP	Uncertain	0.086	D
MetaRNN	Benign	0.020	T;T;T;T;T;T
MetaSVM	Uncertain	0.050	D
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Benign	0.36	T
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	T
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

Other links and lift over

dbSNP: rs41279188; hg19: chr15-75012979;