15-74720599-G-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_001319217.2(CYP1A1):c.1429C>T(p.Arg477Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000157 in 1,614,076 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.00052 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00012 (1 hom.)
• Consequence: CYP1A1 NM_001319217.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.41

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0406335).
• BP6: Variant 15-74720599-G-A is Benign according to our data. Variant chr15-74720599-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 3051186.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYP1A1	NM_001319217.2	c.1429C>T	p.Arg477Trp	missense_variant	7/7	ENST00000379727.8
CYP1A1	NM_000499.5	c.1429C>T	p.Arg477Trp	missense_variant	7/7
CYP1A1	NM_001319216.2	c.1342C>T	p.Arg448Trp	missense_variant	6/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP1A1	ENST00000379727.8	c.1429C>T	p.Arg477Trp	missense_variant	7/7	1	NM_001319217.2	P1

Frequencies

GnomAD3 genomes AF: 0.000519 AC: 79 AN: 152182 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00166

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000207 AC: 52 AN: 251266 Hom.: 1 AF XY: 0.000140 AC XY: 19 AN XY: 135798

Gnomad AFR exome AF: 0.00246

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000119 AC: 174 AN: 1461776 Hom.: 1 Cov.: 30 AF XY: 0.000109 AC XY: 79 AN XY: 727198

Gnomad4 AFR exome AF: 0.00206

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000128

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000648

Gnomad4 OTH exome AF: 0.000232

GnomAD4 genome AF: 0.000519 AC: 79 AN: 152300 Hom.: 1 Cov.: 32 AF XY: 0.000577 AC XY: 43 AN XY: 74476

Gnomad4 AFR AF: 0.00166

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000127 Hom.: 0

Bravo AF: 0.000552

ESP6500AA AF: 0.00319 AC: 14

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000255 AC: 31

EpiCase AF: 0.00

EpiControl AF: 0.000237

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

CYP1A1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 23, 2023

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	0.20
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.24
Cadd	Uncertain	23
Dann	Uncertain	1.0
DEOGEN2	Benign	0.23	T;T;D;D;D;T
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.43	T;T;T;.;.;.
M_CAP	Benign	0.076	D
MetaRNN	Benign	0.041	T;T;T;T;T;T
MetaSVM	Uncertain	-0.067	T
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.21	T
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D
Polyphen		0.99	.;D;D;D;D;D
Vest4		0.24
MVP		0.97
MPC		0.19
ClinPred		0.16	T
GERP RS		4.7
Varity_R		0.49
gMVP		0.57

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: rs56240201; hg19: chr15-75012940; COSMIC: COSV65697213; COSMIC: COSV65697213;