15-74720584-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_001319217.2(CYP1A1):c.1444G>A(p.Val482Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000704 in 1,613,722 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 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 0.00075 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00070 (7 hom.)
• Consequence: CYP1A1 NM_001319217.2 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.00800

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006218821).
• BP6: Variant 15-74720584-C-T is Benign according to our data. Variant chr15-74720584-C-T is described in ClinVar as [Benign]. Clinvar id is 3033158.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAdExome at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYP1A1	NM_001319217.2	c.1444G>A	p.Val482Met	missense_variant	7/7	ENST00000379727.8
CYP1A1	NM_000499.5	c.1444G>A	p.Val482Met	missense_variant	7/7
CYP1A1	NM_001319216.2	c.1357G>A	p.Val453Met	missense_variant	6/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP1A1	ENST00000379727.8	c.1444G>A	p.Val482Met	missense_variant	7/7	1	NM_001319217.2	P1

Frequencies

GnomAD3 genomes AF: 0.000749 AC: 114 AN: 152166 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.0213

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000397

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00110 AC: 275 AN: 250818 Hom.: 3 AF XY: 0.00108 AC XY: 146 AN XY: 135538

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.0203

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.000754

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.000344

Gnomad OTH exome AF: 0.00115

GnomAD4 exome AF: 0.000699 AC: 1022 AN: 1461438 Hom.: 7 Cov.: 31 AF XY: 0.000741 AC XY: 539 AN XY: 726990

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.0229

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000847

Gnomad4 FIN exome AF: 0.0000562

Gnomad4 NFE exome AF: 0.000210

Gnomad4 OTH exome AF: 0.00169

GnomAD4 genome AF: 0.000749 AC: 114 AN: 152284 Hom.: 0 Cov.: 32 AF XY: 0.000725 AC XY: 54 AN XY: 74478

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.000458

Gnomad4 ASJ AF: 0.0213

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.000397

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00118 Hom.: 4

Bravo AF: 0.000740

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000931 AC: 8

ExAC AF: 0.000840 AC: 102

EpiCase AF: 0.000436

EpiControl AF: 0.000533

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

Jun 11, 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	0.15
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.45
Cadd	Benign	16
Dann	Uncertain	1.0
DEOGEN2	Benign	0.022	T;T;T;T;T;T
Eigen	Benign	-0.051
Eigen_PC	Benign	-0.27
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.76	T;T;T;.;.;.
M_CAP	Benign	0.038	D
MetaRNN	Benign	0.0062	T;T;T;T;T;T
MetaSVM	Benign	-0.59	T
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.35	T
Sift4G	Uncertain	0.053	T;T;T;T;T;T
Polyphen		0.99, 0.99	.;D;D;D;D;D
Vest4		0.11
MVP		0.80
MPC		0.054
ClinPred		0.027	T
GERP RS		3.7
Varity_R		0.19
gMVP		0.38

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: rs28399429; hg19: chr15-75012925; COSMIC: COSV65697832; COSMIC: COSV65697832;