15-74720496-C-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001319217.2(CYP1A1):c.1532G>T(p.Arg511Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00128 in 1,566,008 control chromosomes in the GnomAD database, including 54 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00091 (8 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (46 hom.)
• Consequence: CYP1A1 NM_001319217.2 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 6.29

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007909983).
• BP6: Variant 15-74720496-C-A is Benign according to our data. Variant chr15-74720496-C-A is described in ClinVar as [Benign]. Clinvar id is 788807.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000913 (139/152280) while in subpopulation SAS AF= 0.028 (135/4828). AF 95% confidence interval is 0.0241. There are 8 homozygotes in gnomad4. There are 108 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYP1A1	NM_001319217.2	c.1532G>T	p.Arg511Leu	missense_variant	7/7	ENST00000379727.8
CYP1A1	NM_000499.5	c.1532G>T	p.Arg511Leu	missense_variant	7/7
CYP1A1	NM_001319216.2	c.1445G>T	p.Arg482Leu	missense_variant	6/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP1A1	ENST00000379727.8	c.1532G>T	p.Arg511Leu	missense_variant	7/7	1	NM_001319217.2	P1

Frequencies

GnomAD3 genomes AF: 0.000907 AC: 138 AN: 152162 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0277

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.00210 AC: 444 AN: 211494 Hom.: 8 AF XY: 0.00262 AC XY: 293 AN XY: 111858

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000561

Gnomad SAS exome AF: 0.0198

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000207

Gnomad OTH exome AF: 0.000985

GnomAD4 exome AF: 0.00132 AC: 1860 AN: 1413728 Hom.: 46 Cov.: 30 AF XY: 0.00183 AC XY: 1278 AN XY: 697754

Gnomad4 AFR exome AF: 0.0000615

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0216

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000974

Gnomad4 OTH exome AF: 0.00144

GnomAD4 genome AF: 0.000913 AC: 139 AN: 152280 Hom.: 8 Cov.: 32 AF XY: 0.00145 AC XY: 108 AN XY: 74454

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0280

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.000257 Hom.: 1

Bravo AF: 0.000181

ExAC AF: 0.00245 AC: 296

Asia WGS AF: 0.0110 AC: 38 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jun 13, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Benign	0.011	T
BayesDel_noAF	Pathogenic	0.26
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.081	T;T;D;D;D;T
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.63	T;T;T;.;.;.
MetaRNN	Benign	0.0079	T;T;T;T;T;T
MetaSVM	Uncertain	0.30	D
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Benign	0.38	T
Sift4G	Pathogenic	0.0	D;D;D;D;D;D
Polyphen		0.99	.;D;D;D;D;D
Vest4		0.63
MutPred		0.56		.;.;Loss of disorder (P = 0.0822);Loss of disorder (P = 0.0822);Loss of disorder (P = 0.0822);.;
MVP		1.0
MPC		0.23
ClinPred		0.17	T
GERP RS		5.7
Varity_R		0.57
gMVP		0.85

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: rs56343424; hg19: chr15-75012837; COSMIC: COSV65697739; COSMIC: COSV65697739;