rs17861094

chr15-74722865-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001319217.2(CYP1A1):c.233T>C(p.Ile78Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00447 in 1,614,088 control chromosomes in the GnomAD database, including 269 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.023 (133 hom., cov: 32)
  • Exomes 𝑓: 0.0026 (136 hom.)
• Consequence: CYP1A1 NM_001319217.2 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 9.14

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=0.010427326).
• BP6: Variant 15-74722865-A-G is Benign according to our data. Variant chr15-74722865-A-G is described in ClinVar as [Benign]. Clinvar id is 776931.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0777 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYP1A1	NM_001319217.2	c.233T>C	p.Ile78Thr	missense_variant	2/7	ENST00000379727.8
CYP1A1	NM_000499.5	c.233T>C	p.Ile78Thr	missense_variant	2/7
CYP1A1	NM_001319216.2	c.233T>C	p.Ile78Thr	missense_variant	2/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP1A1	ENST00000379727.8	c.233T>C	p.Ile78Thr	missense_variant	2/7	1	NM_001319217.2	P1

Frequencies

GnomAD3 genomes AF: 0.0227 AC: 3457 AN: 152110 Hom.: 133 Cov.: 32

Gnomad AFR AF: 0.0802

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00556

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.0129

GnomAD3 exomes AF: 0.00668 AC: 1679 AN: 251314 Hom.: 64 AF XY: 0.00498 AC XY: 677 AN XY: 135840

Gnomad AFR exome AF: 0.0834

Gnomad AMR exome AF: 0.00359

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00470

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000246

Gnomad OTH exome AF: 0.00424

GnomAD4 exome AF: 0.00257 AC: 3764 AN: 1461862 Hom.: 136 Cov.: 31 AF XY: 0.00226 AC XY: 1647 AN XY: 727240

Gnomad4 AFR exome AF: 0.0853

Gnomad4 AMR exome AF: 0.00429

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00306

Gnomad4 FIN exome AF: 0.0000375

Gnomad4 NFE exome AF: 0.000104

Gnomad4 OTH exome AF: 0.00525

GnomAD4 genome AF: 0.0227 AC: 3457 AN: 152226 Hom.: 133 Cov.: 32 AF XY: 0.0214 AC XY: 1589 AN XY: 74426

Gnomad4 AFR AF: 0.0800

Gnomad4 AMR AF: 0.00556

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000265

Gnomad4 OTH AF: 0.0128

Alfa AF: 0.00400 Hom.: 37

Bravo AF: 0.0259

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0815 AC: 358

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00802 AC: 974

Asia WGS AF: 0.00433 AC: 15 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000415

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

Aug 16, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.68
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.12
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Benign	0.065	T;T;D;D;D;T
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.91	D;D;D;.;.;.
MetaRNN	Benign	0.010	T;T;T;T;T;T
MetaSVM	Benign	-0.50	T
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.53	T
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D
Polyphen		1.0, 1.0	.;D;D;D;D;D
Vest4		0.79
MVP		1.0
MPC		0.25
ClinPred		0.050	T
GERP RS		5.2
Varity_R		0.89
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: rs17861094; hg19: chr15-75015206;