chr15-74720646-G-C

Variant names:

• chr15-74720646-G-C
• rs1799814
• NM_001319217.2:c.1382C>G
• CYP1A1 p.Thr461Ser

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+1 Uncertain · Cold

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 1 classification points (ACGS-UK Somatic Oncogenicity v2025). O3_ModerateB3_Supporting

The NM_001319217.2(CYP1A1):c.1382C>G (p.Thr461Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The gene CYP1A1 is a tumor suppressor gene (CancerMine: 1 TSG, 1 oncogene citations). The gene CYP1A1 is a known oncogene (CancerMine: 1 TSG, 1 oncogene citations). The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. In-silico predictor (REVEL) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.T461N: Benign (ClinVar VariationId 3056253, 0 stars)

• Frequency: Genomes: not found (cov: 32)
• Consequence: CYP1A1 NM_001319217.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.158
• Publications: 1 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]

Classification according to ACGS-UK Somatic Oncogenicity v2025

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 1 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	O3Absent or very rare in population		Absent or extremely rare in gnomAD (AC ≤ 2) — O3 moderate; GnomAD: AF = absent, AC = 0 — absent/extremely rare (O3 moderate [+2])
	B3Computational evidence does not support deleterious effect		Computational evidence does not support a deleterious effect; Missense variant — primary computational scorer does not support an oncogenic/deleterious effect; supports B3

Variant Effect in Transcripts

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

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	CYP1A1 NM_001319217.2	MANE Select	c.1382C>G p.Thr461Ser	missense	Exon 7 of 7	Prot: NP_001306146.1 UniProt:
	CYP1A1 NM_000499.5		c.1382C>G p.Thr461Ser	missense	Exon 7 of 7	Prot: NP_000490.1 UniProt:
	CYP1A1 NM_001319216.2		c.1295C>G p.Thr432Ser	missense	Exon 6 of 6	Prot: NP_001306145.1 UniProt:

CYP1A1 NM_001319217.2

MANE Select

HGVSc / HGVSpc.1382C>Gp.Thr461Ser

Exon rankExon 7 of 7

missense

Prot: NP_001306146.1UniProt: A0N0X8P04798-1

CYP1A1 NM_000499.5

HGVSc / HGVSpc.1382C>Gp.Thr461Ser

Exon rankExon 7 of 7

missense

Prot: NP_000490.1UniProt: A0N0X8P04798-1

CYP1A1 NM_001319216.2

HGVSc / HGVSpc.1295C>Gp.Thr432Ser

Exon rankExon 6 of 6

missense

Prot: NP_001306145.1UniProt: E7EMT5

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	CYP1A1 ENST00000379727.8	TSL:1MANE Select	c.1382C>G p.Thr461Ser	missense	Exon 7 of 7	Prot: ENSP00000369050.3 UniProt:
	CYP1A1 ENST00000395048.6	TSL:1	c.1382C>G p.Thr461Ser	missense	Exon 7 of 7	Prot: ENSP00000378488.2 UniProt:
	CYP1A1 ENST00000567032.5	TSL:1	c.1382C>G p.Thr461Ser	missense	Exon 7 of 7	Prot: ENSP00000456585.1 UniProt:

CYP1A1 ENST00000379727.8

TSL:1MANE Select

HGVSc / HGVSpc.1382C>Gp.Thr461Ser

Exon rankExon 7 of 7

missense

Prot: ENSP00000369050.3UniProt: P04798-1

CYP1A1 ENST00000395048.6

TSL:1

HGVSc / HGVSpc.1382C>Gp.Thr461Ser

Exon rankExon 7 of 7

missense

Prot: ENSP00000378488.2UniProt: P04798-1

CYP1A1 ENST00000567032.5

TSL:1

HGVSc / HGVSpc.1382C>Gp.Thr461Ser

Exon rankExon 7 of 7

missense

Prot: ENSP00000456585.1UniProt: P04798-1

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 3 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 exome	AF:	AC:	Hom:	AN:	Cov:31
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32

Showing 3 sources

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Benign	7.3
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	1.2
DANN	Benign	0.94
DEOGEN2	Benign	0.0072	T
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.29
FATHMM_MKL	Benign	0.65	D
FuncVEP CTI	Benign	0.025
GPN-Star LLR	N/A	-3.1
GPN-Star score	N/A	3.1
LIST_S2	Benign	0.27	T
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.40	T
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	0.12	N
PhyloP100	Benign	0.16
popEVE	Benign	-2.8
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.30	N
REVEL	Benign	0.16
Sift	Benign	0.73	T
Sift4G	Benign	0.74	T
Varity_R	N/A	0.065
VESM-3B	Benign	-4.5

Showing 27 of 27 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.030
SpliceAI score (max)	Benign	0.010	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs1799814;

hg19: chr15-75012987;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar