15-74720640-G-C

Variant names:

• chr15-74720640-G-C
• rs2278970
• NM_001319217.2:c.1388C>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001319217.2(CYP1A1):​c.1388C>G​(p.Ala463Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CYP1A1 NM_001319217.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.447
• Publications: 6 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP1A1	NM_001319217.2	c.1388C>G	p.Ala463Gly	missense_variant	Exon 7 of 7	ENST00000379727.8	NP_001306146.1
CYP1A1	NM_000499.5	c.1388C>G	p.Ala463Gly	missense_variant	Exon 7 of 7		NP_000490.1
CYP1A1	NM_001319216.2	c.1301C>G	p.Ala434Gly	missense_variant	Exon 6 of 6		NP_001306145.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP1A1	ENST00000379727.8	c.1388C>G	p.Ala463Gly	missense_variant	Exon 7 of 7	1	NM_001319217.2	ENSP00000369050.3

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	0.13
BayesDel_addAF	Benign	-0.036	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	6.9
DANN	Benign	0.96
DEOGEN2	Benign	0.030	T;T;T;T;T;T
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.54
FATHMM_MKL	Benign	0.63	D
LIST_S2	Benign	0.73	T;T;T;.;.;.
M_CAP	Benign	0.040	D
MetaRNN	Uncertain	0.66	D;D;D;D;D;D
MetaSVM	Benign	-0.47	T
MutationAssessor	Benign	1.2	.;.;L;L;L;.
PhyloP100		0.45
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.95	.;.;N;N;N;N
REVEL	Uncertain	0.30
Sift	Benign	0.33	.;.;T;T;T;T
Sift4G	Benign	0.36	T;T;T;T;T;T
Polyphen		0.0090, 0.0030	.;B;B;B;B;B
Vest4		0.24
MutPred		0.88		.;.;Loss of catalytic residue at A463 (P = 0.085);Loss of catalytic residue at A463 (P = 0.085);Loss of catalytic residue at A463 (P = 0.085);.;
MVP		1.0
MPC		0.032
ClinPred		0.71	D
GERP RS		-0.30
Varity_R		0.23
gMVP		0.69

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: rs2278970; hg19: chr15-75012981;