rs4646427

Positions:

• chr15-74753351-T-C

Variant summary

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

The NM_000761.5(CYP1A2):​c.1253+81T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0331 in 1,155,044 control chromosomes in the GnomAD database, including 1,084 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 0.048 (255 hom., cov: 30)
  • Exomes 𝑓: 0.031 (829 hom.)
• Consequence: CYP1A2 NM_000761.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.447

Genes affected

CYP1A2 (HGNC:2596): (cytochrome P450 family 1 subfamily A member 2) This gene 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. The protein encoded by this gene 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. Other xenobiotic substrates for this enzyme include caffeine, aflatoxin B1, and acetaminophen. The transcript from this gene contains four Alu sequences flanked by direct repeats in the 3' untranslated region. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0883 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYP1A2	NM_000761.5	c.1253+81T>C		intron_variant		ENST00000343932.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP1A2	ENST00000343932.5	c.1253+81T>C		intron_variant		1	NM_000761.5	P1

Frequencies

GnomAD3 genomes AF: 0.0479 AC: 7280 AN: 152134 Hom.: 255 Cov.: 30

Gnomad AFR AF: 0.0910

Gnomad AMI AF: 0.0231

Gnomad AMR AF: 0.0332

Gnomad ASJ AF: 0.0577

Gnomad EAS AF: 0.0744

Gnomad SAS AF: 0.0844

Gnomad FIN AF: 0.0375

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.0218

Gnomad OTH AF: 0.0426

GnomAD4 exome AF: 0.0308 AC: 30931 AN: 1002792 Hom.: 829 AF XY: 0.0332 AC XY: 17045 AN XY: 512958

Gnomad4 AFR exome AF: 0.0949

Gnomad4 AMR exome AF: 0.0414

Gnomad4 ASJ exome AF: 0.0580

Gnomad4 EAS exome AF: 0.0481

Gnomad4 SAS exome AF: 0.0929

Gnomad4 FIN exome AF: 0.0414

Gnomad4 NFE exome AF: 0.0190

Gnomad4 OTH exome AF: 0.0365

GnomAD4 genome AF: 0.0478 AC: 7277 AN: 152252 Hom.: 255 Cov.: 30 AF XY: 0.0490 AC XY: 3651 AN XY: 74446

Gnomad4 AFR AF: 0.0907

Gnomad4 AMR AF: 0.0331

Gnomad4 ASJ AF: 0.0577

Gnomad4 EAS AF: 0.0738

Gnomad4 SAS AF: 0.0851

Gnomad4 FIN AF: 0.0375

Gnomad4 NFE AF: 0.0218

Gnomad4 OTH AF: 0.0421

Alfa AF: 0.0277 Hom.: 101

Bravo AF: 0.0478

Asia WGS AF: 0.0690 AC: 239 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	2.0
DANN	Benign	0.29

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: rs4646427; hg19: chr15-75045692;