rs4987133

Positions:

• chr15-74721686-A-G

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.857T>C​(p.Ile286Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00101 in 1,614,098 control chromosomes in the GnomAD database, including 10 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 0.0011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0010 (10 hom.)
• Consequence: CYP1A1 NM_001319217.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 7.36

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=0.022174627).
• BP6: Variant 15-74721686-A-G is Benign according to our data. Variant chr15-74721686-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 782007.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYP1A1	NM_001319217.2	c.857T>C	p.Ile286Thr	missense_variant	3/7	ENST00000379727.8	NP_001306146.1
CYP1A1	NM_000499.5	c.857T>C	p.Ile286Thr	missense_variant	3/7		NP_000490.1
CYP1A1	NM_001319216.2	c.857T>C	p.Ile286Thr	missense_variant	3/6		NP_001306145.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYP1A1	ENST00000379727.8	c.857T>C	p.Ile286Thr	missense_variant	3/7	1	NM_001319217.2	ENSP00000369050.3

Frequencies

GnomAD3 genomes AF: 0.00106 AC: 162 AN: 152126 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000218

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00183

Gnomad ASJ AF: 0.0228

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.000485

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00152 AC: 383 AN: 251358 Hom.: 3 AF XY: 0.00149 AC XY: 203 AN XY: 135852

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000521

Gnomad ASJ exome AF: 0.0242

Gnomad EAS exome AF: 0.000272

Gnomad SAS exome AF: 0.000523

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000616

Gnomad OTH exome AF: 0.00424

GnomAD4 exome AF: 0.00100 AC: 1464 AN: 1461852 Hom.: 10 Cov.: 32 AF XY: 0.00107 AC XY: 778 AN XY: 727234

Gnomad4 AFR exome AF: 0.000299

Gnomad4 AMR exome AF: 0.000693

Gnomad4 ASJ exome AF: 0.0253

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.000417

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000415

Gnomad4 OTH exome AF: 0.00301

GnomAD4 genome AF: 0.00108 AC: 164 AN: 152246 Hom.: 0 Cov.: 32 AF XY: 0.000940 AC XY: 70 AN XY: 74448

Gnomad4 AFR AF: 0.000241

Gnomad4 AMR AF: 0.00183

Gnomad4 ASJ AF: 0.0228

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000500

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00197 Hom.: 6

Bravo AF: 0.00130

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.000455 AC: 2

ESP6500EA AF: 0.00151 AC: 13

ExAC AF: 0.00125 AC: 152

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00120

EpiControl AF: 0.00107

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	CYP1A1: BS2 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 06, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.62
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Pathogenic	0.26
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.082	T;T;D;D;D;T;.;T
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.96	D;D;D;.;.;.;D;D
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.022	T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.34	D
MutationAssessor	Pathogenic	3.5	.;.;H;H;H;.;.;.
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-3.9	.;.;D;D;D;D;D;D
REVEL	Pathogenic	0.78
Sift	Pathogenic	0.0	.;.;D;D;D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D;D;T
Polyphen		0.93, 0.85	.;P;P;P;P;P;.;.
Vest4		0.87
MVP		0.99
MPC		0.21
ClinPred		0.10	T
GERP RS		5.0
Varity_R		0.95
gMVP		0.71

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: rs4987133; hg19: chr15-75014027;