15-74722964-C-T

Position:

• chr15-74722964-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_001319217.2(CYP1A1):​c.134G>A​(p.Gly45Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00453 in 1,614,170 control chromosomes in the GnomAD database, including 529 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0049 (53 hom., cov: 32)
  • Exomes 𝑓: 0.0045 (476 hom.)
• Consequence: CYP1A1 NM_001319217.2 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 2.97

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0020495355).
• BP6: Variant 15-74722964-C-T is Benign according to our data. Variant chr15-74722964-C-T is described in ClinVar as [Benign]. Clinvar id is 3058859.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.124 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYP1A1	NM_001319217.2	c.134G>A	p.Gly45Asp	missense_variant	2/7	ENST00000379727.8	NP_001306146.1
CYP1A1	NM_000499.5	c.134G>A	p.Gly45Asp	missense_variant	2/7		NP_000490.1
CYP1A1	NM_001319216.2	c.134G>A	p.Gly45Asp	missense_variant	2/6		NP_001306145.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYP1A1	ENST00000379727.8	c.134G>A	p.Gly45Asp	missense_variant	2/7	1	NM_001319217.2	ENSP00000369050.3

Frequencies

GnomAD3 genomes AF: 0.00494 AC: 751 AN: 152174 Hom.: 53 Cov.: 32

Gnomad AFR AF: 0.000265

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000851

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.132

Gnomad SAS AF: 0.00600

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.0108 AC: 2707 AN: 251386 Hom.: 188 AF XY: 0.0100 AC XY: 1360 AN XY: 135888

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.142

Gnomad SAS exome AF: 0.00199

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00375

GnomAD4 exome AF: 0.00448 AC: 6555 AN: 1461878 Hom.: 476 Cov.: 31 AF XY: 0.00433 AC XY: 3147 AN XY: 727234

Gnomad4 AFR exome AF: 0.000119

Gnomad4 AMR exome AF: 0.000268

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.146

Gnomad4 SAS exome AF: 0.00220

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000558

Gnomad4 OTH exome AF: 0.00796

GnomAD4 genome AF: 0.00494 AC: 752 AN: 152292 Hom.: 53 Cov.: 32 AF XY: 0.00571 AC XY: 425 AN XY: 74458

Gnomad4 AFR AF: 0.000265

Gnomad4 AMR AF: 0.000849

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.132

Gnomad4 SAS AF: 0.00601

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00520

Alfa AF: 0.00458 Hom.: 129

Bravo AF: 0.00645

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000455 AC: 2

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0104 AC: 1261

Asia WGS AF: 0.0430 AC: 150 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

CYP1A1-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 21, 2019

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
AlphaMissense	Pathogenic	0.65
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.083	T;T;D;D;D;T
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Benign	0.51	D
LIST_S2	Benign	0.68	T;T;T;.;.;.
MetaRNN	Benign	0.0020	T;T;T;T;T;T
MetaSVM	Benign	-0.63	T
MutationAssessor	Pathogenic	3.8	.;.;H;H;H;.
PrimateAI	Benign	0.39	T
PROVEAN	Uncertain	-2.5	.;.;N;N;N;N
REVEL	Benign	0.28
Sift	Benign	0.043	.;.;D;D;D;D
Sift4G	Uncertain	0.038	D;D;D;D;D;D
Polyphen		0.85, 0.84	.;P;P;P;P;P
Vest4		0.51
MPC		0.20
ClinPred		0.13	T
GERP RS		4.7
Varity_R		0.86
gMVP		0.76

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: rs4646422; hg19: chr15-75015305; COSMIC: COSV65696637;