chr15-74720646-G-T

Position:

• chr15-74720646-G-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.1382C>A​(p.Thr461Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0392 in 1,614,122 control chromosomes in the GnomAD database, including 1,560 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict 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 0.030 (108 hom., cov: 32)
  • Exomes 𝑓: 0.040 (1452 hom.)
• Consequence: CYP1A1 NM_001319217.2 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.158

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=0.019521713).
• BP6: Variant 15-74720646-G-T is Benign according to our data. Variant chr15-74720646-G-T is described in ClinVar as [Benign]. Clinvar id is 3056253.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.118 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYP1A1	NM_001319217.2	c.1382C>A	p.Thr461Asn	missense_variant	7/7	ENST00000379727.8
CYP1A1	NM_000499.5	c.1382C>A	p.Thr461Asn	missense_variant	7/7
CYP1A1	NM_001319216.2	c.1295C>A	p.Thr432Asn	missense_variant	6/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP1A1	ENST00000379727.8	c.1382C>A	p.Thr461Asn	missense_variant	7/7	1	NM_001319217.2	P1

Frequencies

GnomAD3 genomes AF: 0.0299 AC: 4543 AN: 152156 Hom.: 109 Cov.: 32

Gnomad AFR AF: 0.00854

Gnomad AMI AF: 0.00330

Gnomad AMR AF: 0.0409

Gnomad ASJ AF: 0.0922

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0143

Gnomad FIN AF: 0.0105

Gnomad MID AF: 0.123

Gnomad NFE AF: 0.0431

Gnomad OTH AF: 0.0435

GnomAD3 exomes AF: 0.0309 AC: 7759 AN: 251432 Hom.: 191 AF XY: 0.0316 AC XY: 4300 AN XY: 135890

Gnomad AFR exome AF: 0.00707

Gnomad AMR exome AF: 0.0253

Gnomad ASJ exome AF: 0.0864

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.0169

Gnomad FIN exome AF: 0.0112

Gnomad NFE exome AF: 0.0427

Gnomad OTH exome AF: 0.0450

GnomAD4 exome AF: 0.0402 AC: 58727 AN: 1461848 Hom.: 1452 Cov.: 31 AF XY: 0.0397 AC XY: 28871 AN XY: 727226

Gnomad4 AFR exome AF: 0.00869

Gnomad4 AMR exome AF: 0.0268

Gnomad4 ASJ exome AF: 0.0880

Gnomad4 EAS exome AF: 0.000176

Gnomad4 SAS exome AF: 0.0176

Gnomad4 FIN exome AF: 0.0116

Gnomad4 NFE exome AF: 0.0445

Gnomad4 OTH exome AF: 0.0427

GnomAD4 genome AF: 0.0298 AC: 4541 AN: 152274 Hom.: 108 Cov.: 32 AF XY: 0.0286 AC XY: 2133 AN XY: 74462

Gnomad4 AFR AF: 0.00852

Gnomad4 AMR AF: 0.0409

Gnomad4 ASJ AF: 0.0922

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0145

Gnomad4 FIN AF: 0.0105

Gnomad4 NFE AF: 0.0431

Gnomad4 OTH AF: 0.0435

Alfa AF: 0.0424 Hom.: 426

Bravo AF: 0.0320

TwinsUK AF: 0.0453 AC: 168

ALSPAC AF: 0.0428 AC: 165

ESP6500AA AF: 0.00933 AC: 41

ESP6500EA AF: 0.0485 AC: 417

ExAC AF: 0.0305 AC: 3708

Asia WGS AF: 0.00982 AC: 34 AN: 3478

EpiCase AF: 0.0495

EpiControl AF: 0.0504

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 28, 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	Benign	0.089
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	1.9
DANN	Benign	0.93
DEOGEN2	Benign	0.0094	T;T;T;T;T;T
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.40
FATHMM_MKL	Benign	0.39	N
LIST_S2	Benign	0.29	T;T;T;.;.;.
MetaRNN	Benign	0.020	T;T;T;T;T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.99	.;.;L;L;L;.
MutationTaster	Benign	0.80	N;N;N;N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.54	.;.;N;N;N;N
REVEL	Benign	0.12
Sift	Benign	0.50	.;.;T;T;T;T
Sift4G	Benign	0.52	T;T;T;T;T;T
Polyphen		0.013	.;B;B;B;B;B
Vest4		0.072
MPC		0.033
ClinPred		0.0027	T
GERP RS		2.7
Varity_R		0.10
gMVP		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: rs1799814; hg19: chr15-75012987; COSMIC: COSV65697167; COSMIC: COSV65697167;