15-74720644-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

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. 12/20 in silico tools predict 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.

• Frequency:
  • Genomes: 𝑓 0.063 (874 hom., cov: 32)
  • Exomes 𝑓: 0.056 (5945 hom.)
• Consequence: CYP1A1 NM_001319217.2 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 4.13

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 -14 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 id is 3060599.Status of the report is criteria_provided_single_submitter, 1 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/exons	MANE	UniProt
CYP1A1	NM_001319217.2	c.1384A>G	p.Ile462Val	missense_variant	7/7	ENST00000379727.8
CYP1A1	NM_000499.5	c.1384A>G	p.Ile462Val	missense_variant	7/7
CYP1A1	NM_001319216.2	c.1297A>G	p.Ile433Val	missense_variant	6/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP1A1	ENST00000379727.8	c.1384A>G	p.Ile462Val	missense_variant	7/7	1	NM_001319217.2	P1

Frequencies

GnomAD3 genomes AF: 0.0634 AC: 9646 AN: 152082 Hom.: 868 Cov.: 32

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

GnomAD3 exomes AF: 0.108 AC: 27169 AN: 251354 Hom.: 3595 AF XY: 0.101 AC XY: 13702 AN XY: 135850

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 SAS exome AF: 0.119

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.: 31 AF XY: 0.0565 AC XY: 41084 AN XY: 727208

Gnomad4 AFR exome AF: 0.00962

Gnomad4 AMR exome AF: 0.363

Gnomad4 ASJ exome AF: 0.0341

Gnomad4 EAS exome AF: 0.234

Gnomad4 SAS exome AF: 0.116

Gnomad4 FIN exome AF: 0.0499

Gnomad4 NFE exome AF: 0.0341

Gnomad4 OTH exome AF: 0.0603

GnomAD4 genome AF: 0.0634 AC: 9657 AN: 152200 Hom.: 874 Cov.: 32 AF XY: 0.0697 AC XY: 5185 AN XY: 74412

Gnomad4 AFR AF: 0.0144

Gnomad4 AMR AF: 0.252

Gnomad4 ASJ AF: 0.0317

Gnomad4 EAS AF: 0.242

Gnomad4 SAS AF: 0.119

Gnomad4 FIN AF: 0.0597

Gnomad4 NFE AF: 0.0355

Gnomad4 OTH AF: 0.0749

Alfa AF: 0.0434 Hom.: 760

Bravo AF: 0.0768

TwinsUK AF: 0.0326 AC: 121

ALSPAC AF: 0.0345 AC: 133

ESP6500AA AF: 0.0123 AC: 54

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: criteria provided, single submitter

Submissions by phenotype

CYP1A1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 18, 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	Benign	0.10
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.38
Cadd	Benign	18
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	D
LIST_S2	Benign	0.80	T;D;T;.;.;.
MetaRNN	Benign	0.017	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.0000019	P;P;P;P
PrimateAI	Benign	0.38	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	T
GERP RS		4.5
Varity_R		0.40
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

Other links and lift over

dbSNP: rs1048943; hg19: chr15-75012985; COSMIC: COSV65696797; COSMIC: COSV65696797;