rs4646421

Positions:

• chr15-74723851-G-A
• chr15-74723851-G-C
• chr15-74723851-G-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001319217.2(CYP1A1):​c.-29-725C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.215 in 152,078 control chromosomes in the GnomAD database, including 4,844 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 0.22 (4844 hom., cov: 31)
• Consequence: CYP1A1 NM_001319217.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.265

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.395 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYP1A1	NM_001319217.2	c.-29-725C>T		intron_variant		ENST00000379727.8
CYP1A1	NM_000499.5	c.-26-728C>T		intron_variant
CYP1A1	NM_001319216.2	c.-29-725C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP1A1	ENST00000379727.8	c.-29-725C>T		intron_variant		1	NM_001319217.2	P1

Frequencies

GnomAD3 genomes AF: 0.215 AC: 32628 AN: 151960 Hom.: 4823 Cov.: 31

Gnomad AFR AF: 0.354

Gnomad AMI AF: 0.119

Gnomad AMR AF: 0.348

Gnomad ASJ AF: 0.125

Gnomad EAS AF: 0.410

Gnomad SAS AF: 0.302

Gnomad FIN AF: 0.122

Gnomad MID AF: 0.142

Gnomad NFE AF: 0.0996

Gnomad OTH AF: 0.212

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

GnomAD4 genome AF: 0.215 AC: 32708 AN: 152078 Hom.: 4844 Cov.: 31 AF XY: 0.221 AC XY: 16410 AN XY: 74358

Gnomad4 AFR AF: 0.354

Gnomad4 AMR AF: 0.349

Gnomad4 ASJ AF: 0.125

Gnomad4 EAS AF: 0.410

Gnomad4 SAS AF: 0.305

Gnomad4 FIN AF: 0.122

Gnomad4 NFE AF: 0.0995

Gnomad4 OTH AF: 0.218

Alfa AF: 0.123 Hom.: 2148

Bravo AF: 0.236

Asia WGS AF: 0.419 AC: 1452 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	4.9
DANN	Benign	0.68

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: rs4646421; hg19: chr15-75016192;