rs2229150

chr15-74722821-G-Achr15-74722821-G-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001319217.2(CYP1A1):c.277C>T(p.Arg93Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000783 in 1,614,006 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. 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. R93Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00062 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00080 (2 hom.)
• Consequence: CYP1A1 NM_001319217.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.290

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 -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.12483463).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYP1A1	NM_001319217.2	c.277C>T	p.Arg93Trp	missense_variant	2/7	ENST00000379727.8
CYP1A1	NM_000499.5	c.277C>T	p.Arg93Trp	missense_variant	2/7
CYP1A1	NM_001319216.2	c.277C>T	p.Arg93Trp	missense_variant	2/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP1A1	ENST00000379727.8	c.277C>T	p.Arg93Trp	missense_variant	2/7	1	NM_001319217.2	P1

Frequencies

GnomAD3 genomes AF: 0.000624 AC: 95 AN: 152136 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000266

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000956

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000685 AC: 172 AN: 251228 Hom.: 0 AF XY: 0.000729 AC XY: 99 AN XY: 135862

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000376

Gnomad ASJ exome AF: 0.000397

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000817

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.00107

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000799 AC: 1168 AN: 1461752 Hom.: 2 Cov.: 31 AF XY: 0.000791 AC XY: 575 AN XY: 727188

Gnomad4 AFR exome AF: 0.000149

Gnomad4 AMR exome AF: 0.000402

Gnomad4 ASJ exome AF: 0.000344

Gnomad4 EAS exome AF: 0.000327

Gnomad4 SAS exome AF: 0.000812

Gnomad4 FIN exome AF: 0.0000751

Gnomad4 NFE exome AF: 0.000910

Gnomad4 OTH exome AF: 0.000497

GnomAD4 genome AF: 0.000624 AC: 95 AN: 152254 Hom.: 1 Cov.: 32 AF XY: 0.000618 AC XY: 46 AN XY: 74440

Gnomad4 AFR AF: 0.000265

Gnomad4 AMR AF: 0.00105

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000956

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000899 Hom.: 0

Bravo AF: 0.000582

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00105 AC: 9

ExAC AF: 0.000749 AC: 91

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000818

EpiControl AF: 0.000652

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.22
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.21	T;T;D;D;D;T
Eigen	Uncertain	0.23
Eigen_PC	Benign	-0.012
FATHMM_MKL	Benign	0.41	N
LIST_S2	Uncertain	0.93	D;D;D;.;.;.
M_CAP	Benign	0.057	D
MetaRNN	Benign	0.12	T;T;T;T;T;T
MetaSVM	Uncertain	0.22	D
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Benign	0.30	T
Sift4G	Pathogenic	0.0	D;D;D;D;D;D
Polyphen		1.0, 1.0	.;D;D;D;D;D
Vest4		0.37
MVP		0.97
MPC		0.034
ClinPred		0.11	T
GERP RS		-1.1
Varity_R		0.66
gMVP		0.77

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: rs2229150; hg19: chr15-75015162;