rs1048943

Positions:

• chr15-74720644-T-A
• chr15-74720644-T-C
• chr15-74720644-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001319217.2(CYP1A1):​c.1384A>T​(p.Ile462Phe) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I462V) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CYP1A1 NM_001319217.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.13

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.869

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYP1A1	NM_001319217.2	c.1384A>T	p.Ile462Phe	missense_variant	7/7	ENST00000379727.8	NP_001306146.1
CYP1A1	NM_000499.5	c.1384A>T	p.Ile462Phe	missense_variant	7/7		NP_000490.1
CYP1A1	NM_001319216.2	c.1297A>T	p.Ile433Phe	missense_variant	6/6		NP_001306145.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYP1A1	ENST00000379727.8	c.1384A>T	p.Ile462Phe	missense_variant	7/7	1	NM_001319217.2	ENSP00000369050	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Uncertain	0.090	D
BayesDel_noAF	Benign	-0.11
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.057	T;T;T;T;T;T
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.84	T;D;D;.;.;.
M_CAP	Benign	0.048	D
MetaRNN	Pathogenic	0.87	D;D;D;D;D;D
MetaSVM	Benign	-0.54	T
MutationAssessor	Uncertain	2.8	.;.;M;M;M;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-2.5	.;.;D;D;D;N
REVEL	Benign	0.27
Sift	Uncertain	0.021	.;.;D;D;D;D
Sift4G	Uncertain	0.014	D;D;D;D;D;D
Polyphen		0.87, 0.79	.;P;P;P;P;P
Vest4		0.72
MutPred		0.43		.;.;Loss of catalytic residue at I462 (P = 0.102);Loss of catalytic residue at I462 (P = 0.102);Loss of catalytic residue at I462 (P = 0.102);.;
MVP		1.0
MPC		0.22
ClinPred		0.98	D
GERP RS		4.5
Varity_R		0.82
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: rs1048943; hg19: chr15-75012985;