NM_001319217.2:c.1382C>A

Variant names:

• chr15-74720646-G-T
• rs1799814
• NM_001319217.2:c.1382C>A
• CYP1A1 p.Thr461Asn

GermlineCancer (beta)

Variant summary

Our verdict is Benign.

<-10 Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -11 classification points (ACMG Germline Pathogenicity v2019). BA1BP4_ModerateBP6

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 cumulative frequency of 0.0392 (AC=63,268) in the gnomAD database across 1,614,122 control chromosomes, including 1,560 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.118. In-silico predictor (REVEL) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign/Likely Benign (no review stars). This exact variant is curated in the UniProt human variants database as Uncertain Significance; it is also listed as a COSMIC curated somatic variant.

• 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
• Publications: 65 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 ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Benign. The variant received -11 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Moderate).
	BP6Reputable source reports benign		ClinVar 0-star benign — supporting (BP6); ClinVar germline classification: Benign/Likely Benign, 0 star(s).
	BA1Stand-alone benign allele frequency (>5%)		GnomAD effective popmax AF >5% — BA1 stand-alone benign; GnomAD reliable popmax AF = 0.1175 — exceeds 5%% threshold (BA1 applied)

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>A p.Thr461Asn	missense	Exon 7 of 7	Prot: NP_001306146.1 UniProt:
	CYP1A1 NM_000499.5		c.1382C>A p.Thr461Asn	missense	Exon 7 of 7	Prot: NP_000490.1 UniProt:
	CYP1A1 NM_001319216.2		c.1295C>A p.Thr432Asn	missense	Exon 6 of 6	Prot: NP_001306145.1 UniProt:

CYP1A1 NM_001319217.2

MANE Select

HGVSc / HGVSpc.1382C>Ap.Thr461Asn

Exon rankExon 7 of 7

missense

Prot: NP_001306146.1UniProt: A0N0X8P04798-1

CYP1A1 NM_000499.5

HGVSc / HGVSpc.1382C>Ap.Thr461Asn

Exon rankExon 7 of 7

missense

Prot: NP_000490.1UniProt: A0N0X8P04798-1

CYP1A1 NM_001319216.2

HGVSc / HGVSpc.1295C>Ap.Thr432Asn

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>A p.Thr461Asn	missense	Exon 7 of 7	Prot: ENSP00000369050.3 UniProt:
	CYP1A1 ENST00000395048.6	TSL:1	c.1382C>A p.Thr461Asn	missense	Exon 7 of 7	Prot: ENSP00000378488.2 UniProt:
	CYP1A1 ENST00000567032.5	TSL:1	c.1382C>A p.Thr461Asn	missense	Exon 7 of 7	Prot: ENSP00000456585.1 UniProt:

CYP1A1 ENST00000379727.8

TSL:1MANE Select

HGVSc / HGVSpc.1382C>Ap.Thr461Asn

Exon rankExon 7 of 7

missense

Prot: ENSP00000369050.3UniProt: P04798-1

CYP1A1 ENST00000395048.6

TSL:1

HGVSc / HGVSpc.1382C>Ap.Thr461Asn

Exon rankExon 7 of 7

missense

Prot: ENSP00000378488.2UniProt: P04798-1

CYP1A1 ENST00000567032.5

TSL:1

HGVSc / HGVSpc.1382C>Ap.Thr461Asn

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 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.0299	AC:4543	Hom:109	AN:152156	Cov:32
GnomAD2 exomes	AF: 0.0309	AC:7759	Hom:	AN:251432	Cov:
GnomAD4 exome	AF: 0.0402	AC:58727	Hom:1452	AN:1461848	Cov:31
GnomAD4 genome	AF: 0.0298	AC:4541	Hom:108	AN:152274	Cov:32
TOPMed (Bravo)	AF: 0.0320	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.0400	AC:24226	Hom:684	AN:605178	Cov:
Local & regional cohorts 11 sources Population-specific and national genomic databases
ABraOM SABE-WGS-1171	AF: 0.0525	AC:123	Hom:3	AN:2342	Cov:
ChinaMAP Phase 1	AF: 0.000542	AC:	Hom:	AN:	Cov:
Denmark Genome	AF: 0.0667	AC:20	Hom:	AN:300	Cov:
ESP6500 (Exome Variant Server)	AF: 0.0353	AC:458	Hom:	AN:12986	Cov:
GenomeAsia100K	AF: 0.00982	AC:34	Hom:	AN:3478	Cov:
Korea4K (4,157 Koreans)	AF: 0.000276	AC:2	Hom:	AN:7234	Cov:
Qatari Genome	AF: 0.188	AC:378	Hom:	AN:2010	Cov:
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.0000490	AC:6	Hom:0	AN:122588	Cov:
Turkish Variome	AF: 0.0635	AC:427	Hom:21	AN:6722	Cov:
UK10K	AF: 0.0440	AC:333	Hom:	AN:7562	Cov:
WBBC (Westlake BioBank for Chinese) pilot	AF: 0.000446	AC:4	Hom:0	AN:8960	Cov:

Showing 17 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
ASC(Autism)	0.0378 *	416	11014	0.0399 *	698	17498
BipEx(Bipolar disorder (including schizoaffective))	0.0384	1092	28420	0.0391	1129	28844
Epi25(Epilepsy)	0.0373	1563	41956	0.0385	2578	66888
SCHEMA(Schizophrenia)	0.0369	4562	123782	0.0435	8547	196466

Showing 4 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Benign

Revision: no assertion criteria provided

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

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Benign	7.6
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
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.40
FATHMM_MKL	Benign	0.39	N
FuncVEP CTI	Benign	0.018
GPN-Star LLR	N/A	-2.8
GPN-Star score	N/A	2.8
LIST_S2	Benign	0.29	T
MetaRNN	Benign	0.020	T
MetaSVM	Benign	-0.90	T
Mutation Taster	N/A	96/4	polymorphism (auto)
MutationAssessor	Benign	0.99	L
PhyloP100	Benign	0.16
popEVE	Benign	-2.8
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.54	N
REVEL	Benign	0.12
Sift	Benign	0.50	T
Sift4G	Benign	0.52	T
Varity_R	N/A	0.10
VESM-3B	Benign	-6.5

Showing 27 of 27 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.040
SpliceAI score (max)	Benign	0.0	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;

COSMIC: COSV65697167;

COSMIC: COSV65697167;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

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