NM_001319217.2:c.*1189T>C

Variant names:

• chr15-74719300-A-G
• rs4646903
• NM_001319217.2:c.*1189T>C

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 -12 classification points (ACMG Germline Pathogenicity v2019). BA1BP4_Strong

The NM_001319217.2(CYP1A1):c.*1189T>C variant causes a downstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.184 (AC=27,847) in the gnomAD database across 150,994 control chromosomes, including 3,358 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.4. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.18 (3358 hom., cov: 30)
• Consequence: CYP1A1 NM_001319217.2 downstream_gene
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.929
• Publications: 198 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 -12 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); No splicing predictor data available.; Germline computational verdict: benign (Strong).
	BA1Stand-alone benign allele frequency (>5%)		GnomAD effective popmax AF >5% — BA1 stand-alone benign; GnomAD reliable popmax AF = 0.4004 — 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.*1189T>C	downstream_gene	N/A	Prot: NP_001306146.1 UniProt:
	CYP1A1 NM_000499.5		c.*1189T>C	downstream_gene	N/A	Prot: NP_000490.1 UniProt:
	CYP1A1 NM_001319216.2		c.*1189T>C	downstream_gene	N/A	Prot: NP_001306145.1 UniProt:

CYP1A1 NM_001319217.2

MANE Select

HGVSc / HGVSpc.*1189T>C

Exon rankN/A

downstream_gene

Prot: NP_001306146.1UniProt: A0N0X8P04798-1

CYP1A1 NM_000499.5

HGVSc / HGVSpc.*1189T>C

Exon rankN/A

downstream_gene

Prot: NP_000490.1UniProt: A0N0X8P04798-1

CYP1A1 NM_001319216.2

HGVSc / HGVSpc.*1189T>C

Exon rankN/A

downstream_gene

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.*1189T>C	downstream_gene	N/A	Prot: ENSP00000369050.3 UniProt:
	CYP1A1 ENST00000395048.6	TSL:1	c.*1189T>C	downstream_gene	N/A	Prot: ENSP00000378488.2 UniProt:
	CYP1A1 ENST00000853120.1		c.*1189T>C	downstream_gene	N/A	Prot: ENSP00000523179.1 UniProt:

CYP1A1 ENST00000379727.8

TSL:1MANE Select

HGVSc / HGVSpc.*1189T>C

Exon rankN/A

downstream_gene

Prot: ENSP00000369050.3UniProt: P04798-1

CYP1A1 ENST00000395048.6

TSL:1

HGVSc / HGVSpc.*1189T>C

Exon rankN/A

downstream_gene

Prot: ENSP00000378488.2UniProt: P04798-1

CYP1A1 ENST00000853120.1

HGVSc / HGVSpc.*1189T>C

Exon rankN/A

downstream_gene

Prot: ENSP00000523179.1UniProt: 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 4 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.184	AC:27781	Hom:3337	AN:150878	Cov:30
GnomAD4 genome	AF: 0.184	AC:27847	Hom:3358	AN:150994	Cov:30
TOPMed (Bravo)	AF: 0.200	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.148	AC:3663	Hom:348	AN:24820	Cov:
Local & regional cohorts 9 sources Population-specific and national genomic databases
ABraOM SABE-WGS-1171	AF: 0.210	AC:491	Hom:59	AN:2342	Cov:
ChinaMAP Phase 1	AF: 0.409	AC:	Hom:	AN:	Cov:
Denmark Genome	AF: 0.142	AC:33	Hom:	AN:232	Cov:
GenomeAsia100K	AF: 0.417	AC:1448	Hom:	AN:3478	Cov:
Korea4K (4,157 Koreans)	AF: 0.379	AC:2737	Hom:	AN:7216	Cov:
Qatari Genome	AF: 0.136	AC:24	Hom:	AN:176	Cov:
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.376	AC:43893	Hom:8050	AN:116610	Cov:
Turkish Variome	AF: 0.159	AC:246	Hom:24	AN:1546	Cov:
UK10K	AF: 0.107	AC:808	Hom:	AN:7562	Cov:

Showing 13 sources

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Benign	4.4
BayesDel_noAF	Benign	-0.91
CADD	Benign	3.4
DANN	Benign	0.46
GPN-Star LLR	N/A	-0.57
GPN-Star score	N/A	0.57
PhyloP100	Benign	0.93

Showing 7 of 7 scores

Splicing Scores

No splicing scores have been computed for this variant.

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: rs4646903;

hg19: chr15-75011641;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar