rs4646903

Variant names:

• chr15-74719300-A-G
• rs4646903
• NM_001319217.2:c.*1189T>C

Your query was ambiguous. Multiple possible variants found:

• chr15-74719300-A-G
• chr15-74719300-A-T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001319217.2(CYP1A1):​c.*1189T>C variant causes a downstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.184 in 150,994 control chromosomes in the GnomAD database, including 3,358 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.

• Frequency: Genomes: 𝑓 0.18 (3358 hom., cov: 30)
• Consequence: CYP1A1 NM_001319217.2 downstream_gene
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.929
• Publications: 395 publications found

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

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.4 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP1A1	NM_001319217.2	c.*1189T>C		downstream_gene_variant		ENST00000379727.8	NP_001306146.1
CYP1A1	NM_000499.5	c.*1189T>C		downstream_gene_variant			NP_000490.1
CYP1A1	NM_001319216.2	c.*1189T>C		downstream_gene_variant			NP_001306145.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP1A1	ENST00000379727.8	c.*1189T>C		downstream_gene_variant		1	NM_001319217.2	ENSP00000369050.3
CYP1A1	ENST00000395048.6	c.*1189T>C		downstream_gene_variant		1		ENSP00000378488.2
CYP1A1	ENST00000617691.4	c.*1189T>C		downstream_gene_variant		5		ENSP00000482863.1

Frequencies

GnomAD3 genomes AF: 0.184 AC: 27781 AN: 150878 Hom.: 3337 Cov.: 30

Gnomad AFR AF: 0.239

Gnomad AMI AF: 0.120

Gnomad AMR AF: 0.341

Gnomad ASJ AF: 0.123

Gnomad EAS AF: 0.415

Gnomad SAS AF: 0.324

Gnomad FIN AF: 0.128

Gnomad MID AF: 0.158

Gnomad NFE AF: 0.101

Gnomad OTH AF: 0.190

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.184 AC: 27847 AN: 150994 Hom.: 3358 Cov.: 30 AF XY: 0.192 AC XY: 14123 AN XY: 73746

African (AFR) AF: 0.239 AC: 9810 AN: 41096

American (AMR) AF: 0.342 AC: 5171 AN: 15136

Ashkenazi Jewish (ASJ) AF: 0.123 AC: 426 AN: 3456

East Asian (EAS) AF: 0.415 AC: 2121 AN: 5110

South Asian (SAS) AF: 0.327 AC: 1550 AN: 4746

European-Finnish (FIN) AF: 0.128 AC: 1332 AN: 10388

Middle Eastern (MID) AF: 0.163 AC: 48 AN: 294

European-Non Finnish (NFE) AF: 0.101 AC: 6869 AN: 67764

Other (OTH) AF: 0.196 AC: 412 AN: 2102

Alfa AF: 0.137 Hom.: 244

Bravo AF: 0.200

Asia WGS AF: 0.417 AC: 1448 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	3.4
DANN	Benign	0.46
PhyloP100		0.93

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs4646903; hg19: chr15-75011641;