15-74720555-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001319217.2(CYP1A1):c.1473C>T(p.Thr491=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000897 in 1,611,196 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0018 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00080 (22 hom.)
• Consequence: CYP1A1 NM_001319217.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.729

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 15-74720555-G-A is Benign according to our data. Variant chr15-74720555-G-A is described in ClinVar as [Benign]. Clinvar id is 784617.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.729 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00184 (280/152282) while in subpopulation AMR AF= 0.0178 (272/15298). AF 95% confidence interval is 0.016. There are 3 homozygotes in gnomad4. There are 182 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYP1A1	NM_001319217.2	c.1473C>T	p.Thr491=	synonymous_variant	7/7	ENST00000379727.8
CYP1A1	NM_000499.5	c.1473C>T	p.Thr491=	synonymous_variant	7/7
CYP1A1	NM_001319216.2	c.1386C>T	p.Thr462=	synonymous_variant	6/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP1A1	ENST00000379727.8	c.1473C>T	p.Thr491=	synonymous_variant	7/7	1	NM_001319217.2	P1

Frequencies

GnomAD3 genomes AF: 0.00183 AC: 279 AN: 152164 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0177

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00394 AC: 979 AN: 248284 Hom.: 19 AF XY: 0.00313 AC XY: 419 AN XY: 134010

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.0280

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000178

Gnomad OTH exome AF: 0.00198

GnomAD4 exome AF: 0.000799 AC: 1165 AN: 1458914 Hom.: 22 Cov.: 31 AF XY: 0.000668 AC XY: 485 AN XY: 725516

Gnomad4 AFR exome AF: 0.000149

Gnomad4 AMR exome AF: 0.0255

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.000382

GnomAD4 genome AF: 0.00184 AC: 280 AN: 152282 Hom.: 3 Cov.: 32 AF XY: 0.00244 AC XY: 182 AN XY: 74464

Gnomad4 AFR AF: 0.000193

Gnomad4 AMR AF: 0.0178

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000830 Hom.: 0

Bravo AF: 0.00285

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jul 16, 2018

- -

CYP1A1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 24, 2020

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
Cadd	Benign	0.62
Dann	Benign	0.43

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: rs45460597; hg19: chr15-75012896;