rs4646421

Variant names:

• chr15-74723851-G-A
• rs4646421
• NM_001319217.2:c.-29-725C>T

Your query was ambiguous. Multiple possible variants found:

• chr15-74723851-G-A
• chr15-74723851-G-C
• chr15-74723851-G-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.-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
• Publications: 69 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=-0.78).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.395 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001319217.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP1A1	NM_001319217.2	MANE Select	c.-29-725C>T		intron	N/A	NP_001306146.1	P04798-1
	CYP1A1	NM_000499.5		c.-26-728C>T		intron	N/A	NP_000490.1	A0N0X8
	CYP1A1	NM_001319216.2		c.-29-725C>T		intron	N/A	NP_001306145.1	E7EMT5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP1A1	ENST00000379727.8	TSL:1 MANE Select	c.-29-725C>T		intron	N/A	ENSP00000369050.3	P04798-1
	CYP1A1	ENST00000395048.6	TSL:1	c.-26-728C>T		intron	N/A	ENSP00000378488.2	P04798-1
	CYP1A1	ENST00000567032.5	TSL:1	c.-29-725C>T		intron	N/A	ENSP00000456585.1	P04798-1

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

African (AFR) AF: 0.354 AC: 14686 AN: 41442

American (AMR) AF: 0.349 AC: 5332 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.125 AC: 433 AN: 3468

East Asian (EAS) AF: 0.410 AC: 2120 AN: 5172

South Asian (SAS) AF: 0.305 AC: 1466 AN: 4808

European-Finnish (FIN) AF: 0.122 AC: 1291 AN: 10584

Middle Eastern (MID) AF: 0.150 AC: 44 AN: 294

European-Non Finnish (NFE) AF: 0.0995 AC: 6769 AN: 68006

Other (OTH) AF: 0.218 AC: 459 AN: 2110

Alfa AF: 0.141 Hom.: 4288

Bravo AF: 0.236

Asia WGS AF: 0.419 AC: 1452 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	4.9
DANN	Benign	0.68
PhyloP100		-0.27
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4646421; hg19: chr15-75016192;