chr15-74753351-T-C

Variant names:

• chr15-74753351-T-C
• rs4646427
• NM_000761.5:c.1253+81T>C

Variant summary

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

The ENST00000343932.5(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 ENST00000343932.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.447
• Publications: 23 publications found

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

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000343932.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP1A2	NM_000761.5	MANE Select	c.1253+81T>C		intron	N/A	NP_000752.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP1A2	ENST00000343932.5	TSL:1 MANE Select	c.1253+81T>C		intron	N/A	ENSP00000342007.4

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

African (AFR) AF: 0.0949 AC: 2259 AN: 23798

American (AMR) AF: 0.0414 AC: 1544 AN: 37332

Ashkenazi Jewish (ASJ) AF: 0.0580 AC: 1251 AN: 21584

East Asian (EAS) AF: 0.0481 AC: 1703 AN: 35402

South Asian (SAS) AF: 0.0929 AC: 6566 AN: 70698

European-Finnish (FIN) AF: 0.0414 AC: 2071 AN: 50048

Middle Eastern (MID) AF: 0.0623 AC: 299 AN: 4800

European-Non Finnish (NFE) AF: 0.0190 AC: 13601 AN: 714228

Other (OTH) AF: 0.0365 AC: 1637 AN: 44902

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

African (AFR) AF: 0.0907 AC: 3769 AN: 41532

American (AMR) AF: 0.0331 AC: 506 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0577 AC: 200 AN: 3468

East Asian (EAS) AF: 0.0738 AC: 383 AN: 5190

South Asian (SAS) AF: 0.0851 AC: 410 AN: 4816

European-Finnish (FIN) AF: 0.0375 AC: 398 AN: 10618

Middle Eastern (MID) AF: 0.0646 AC: 19 AN: 294

European-Non Finnish (NFE) AF: 0.0218 AC: 1482 AN: 68014

Other (OTH) AF: 0.0421 AC: 89 AN: 2112

Alfa AF: 0.0340 Hom.: 279

Bravo AF: 0.0478

Asia WGS AF: 0.0690 AC: 239 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	2.0
DANN	Benign	0.29
PhyloP100		-0.45
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: rs4646427; hg19: chr15-75045692;