NM_001319217.2:c.134G>A

Variant names:

• chr15-74722964-C-T
• rs4646422
• NM_001319217.2:c.134G>A

Variant summary

Our verdict is Benign. The variant received -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).

• 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
• Publications: 53 publications found

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

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001319217.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP1A1	NM_001319217.2	MANE Select	c.134G>A	p.Gly45Asp	missense	Exon 2 of 7	NP_001306146.1	P04798-1
	CYP1A1	NM_000499.5		c.134G>A	p.Gly45Asp	missense	Exon 2 of 7	NP_000490.1	A0N0X8
	CYP1A1	NM_001319216.2		c.134G>A	p.Gly45Asp	missense	Exon 2 of 6	NP_001306145.1	E7EMT5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP1A1	ENST00000379727.8	TSL:1 MANE Select	c.134G>A	p.Gly45Asp	missense	Exon 2 of 7	ENSP00000369050.3	P04798-1
	CYP1A1	ENST00000395048.6	TSL:1	c.134G>A	p.Gly45Asp	missense	Exon 2 of 7	ENSP00000378488.2	P04798-1
	CYP1A1	ENST00000567032.5	TSL:1	c.134G>A	p.Gly45Asp	missense	Exon 2 of 7	ENSP00000456585.1	P04798-1

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

GnomAD2 exomes AF: 0.0108 AC: 2707 AN: 251386 AF XY: 0.0100

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 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

African (AFR) AF: 0.000119 AC: 4 AN: 33480

American (AMR) AF: 0.000268 AC: 12 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.146 AC: 5802 AN: 39700

South Asian (SAS) AF: 0.00220 AC: 190 AN: 86258

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53416

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5768

European-Non Finnish (NFE) AF: 0.0000558 AC: 62 AN: 1112000

Other (OTH) AF: 0.00796 AC: 481 AN: 60396

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

African (AFR) AF: 0.000265 AC: 11 AN: 41560

American (AMR) AF: 0.000849 AC: 13 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.132 AC: 684 AN: 5166

South Asian (SAS) AF: 0.00601 AC: 29 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68036

Other (OTH) AF: 0.00520 AC: 11 AN: 2114

Alfa AF: 0.00431 Hom.: 228

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

ClinVar submissions

Significance: Benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	CYP1A1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Benign	0.51	D
LIST_S2	Benign	0.68	T
MetaRNN	Benign	0.0020	T
MetaSVM	Benign	-0.63	T
MutationAssessor	Pathogenic	3.8	H
PhyloP100		3.0
PrimateAI	Benign	0.39	T
PROVEAN	Uncertain	-2.5	N
REVEL	Benign	0.28
Sift	Benign	0.043	D
Sift4G	Uncertain	0.038	D
Polyphen		0.85	P
Vest4		0.51
MPC		0.20
ClinPred		0.13	T
GERP RS		4.7
Varity_R		0.86
gMVP		0.76
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

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