15-74752059-G-C

Variant names:

• chr15-74752059-G-C
• rs3743484
• NM_000761.5:c.1043-65G>C

Variant summary

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

The NM_000761.5(CYP1A2):​c.1043-65G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0432 in 1,603,436 control chromosomes in the GnomAD database, including 3,192 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 0.041 (259 hom., cov: 32)
  • Exomes 𝑓: 0.043 (2933 hom.)
• Consequence: CYP1A2 NM_000761.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.45
• Publications: 21 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=-0.92).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.196 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000761.5. 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
	CYP1A2	NM_000761.5	MANE Select	c.1043-65G>C		intron	N/A	NP_000752.2	P05177

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP1A2	ENST00000343932.5	TSL:1 MANE Select	c.1043-65G>C		intron	N/A	ENSP00000342007.4	P05177
	CYP1A2	ENST00000872480.1		c.1058-65G>C		intron	N/A	ENSP00000542539.1
	CYP1A2	ENST00000872476.1		c.1043-65G>C		intron	N/A	ENSP00000542535.1

Frequencies

GnomAD3 genomes AF: 0.0408 AC: 6201 AN: 152132 Hom.: 254 Cov.: 32

Gnomad AFR AF: 0.0291

Gnomad AMI AF: 0.0351

Gnomad AMR AF: 0.0408

Gnomad ASJ AF: 0.0435

Gnomad EAS AF: 0.151

Gnomad SAS AF: 0.206

Gnomad FIN AF: 0.0326

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0289

Gnomad OTH AF: 0.0440

GnomAD4 exome AF: 0.0435 AC: 63122 AN: 1451186 Hom.: 2933 Cov.: 31 AF XY: 0.0476 AC XY: 34310 AN XY: 721234

African (AFR) AF: 0.0255 AC: 847 AN: 33280

American (AMR) AF: 0.0416 AC: 1820 AN: 43768

Ashkenazi Jewish (ASJ) AF: 0.0409 AC: 1026 AN: 25112

East Asian (EAS) AF: 0.149 AC: 5923 AN: 39632

South Asian (SAS) AF: 0.187 AC: 15806 AN: 84328

European-Finnish (FIN) AF: 0.0305 AC: 1604 AN: 52608

Middle Eastern (MID) AF: 0.0426 AC: 243 AN: 5706

European-Non Finnish (NFE) AF: 0.0293 AC: 32432 AN: 1106816

Other (OTH) AF: 0.0571 AC: 3421 AN: 59936

GnomAD4 genome AF: 0.0409 AC: 6224 AN: 152250 Hom.: 259 Cov.: 32 AF XY: 0.0448 AC XY: 3336 AN XY: 74452

African (AFR) AF: 0.0291 AC: 1207 AN: 41524

American (AMR) AF: 0.0409 AC: 626 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0435 AC: 151 AN: 3470

East Asian (EAS) AF: 0.152 AC: 785 AN: 5176

South Asian (SAS) AF: 0.207 AC: 998 AN: 4824

European-Finnish (FIN) AF: 0.0326 AC: 346 AN: 10618

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0289 AC: 1964 AN: 68018

Other (OTH) AF: 0.0511 AC: 108 AN: 2112

Alfa AF: 0.0158 Hom.: 11

Bravo AF: 0.0369

Asia WGS AF: 0.235 AC: 814 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.0050
DANN	Benign	0.63
PhyloP100		-2.5
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: rs3743484; hg19: chr15-75044400; COSMIC: COSV59659305;