NM_001319217.2:c.-29-725C>A

Variant names:

• chr15-74723851-G-T
• rs4646421
• NM_001319217.2:c.-29-725C>A

GermlineCancer (beta)

Variant summary

Our verdict is Likely benign.

-2 Likely Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -2 classification points (ACMG Germline Pathogenicity v2019). PM2BP4_Strong

The NM_001319217.2(CYP1A1):c.-29-725C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. In-silico predictor (BayesDel (noAF)) 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.

• Frequency: Genomes: not found (cov: 31)
• Consequence: CYP1A1 NM_001319217.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.265
• Publications: 3 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: Likely_benign. The variant received -2 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM2Absent/extremely low in population databases		Absent from gnomAD (AR/unknown gene) — PM2; Absent from gnomAD at well-covered site (MOI: unknown) (threshold 0.001) — PM2 moderate.
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Strong).

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.-29-725C>A	intron	Intron 1 of 6	Prot: NP_001306146.1 UniProt:
	CYP1A1 NM_000499.5		c.-26-728C>A	intron	Intron 1 of 6	Prot: NP_000490.1 UniProt:
	CYP1A1 NM_001319216.2		c.-29-725C>A	intron	Intron 1 of 5	Prot: NP_001306145.1 UniProt:

CYP1A1 NM_001319217.2

MANE Select

HGVSc / HGVSpc.-29-725C>A

Exon rankIntron 1 of 6

intron

Prot: NP_001306146.1UniProt: A0N0X8P04798-1

CYP1A1 NM_000499.5

HGVSc / HGVSpc.-26-728C>A

Exon rankIntron 1 of 6

intron

Prot: NP_000490.1UniProt: A0N0X8P04798-1

CYP1A1 NM_001319216.2

HGVSc / HGVSpc.-29-725C>A

Exon rankIntron 1 of 5

intron

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.-29-725C>A	intron	Intron 1 of 6	Prot: ENSP00000369050.3 UniProt:
	CYP1A1 ENST00000395048.6	TSL:1	c.-26-728C>A	intron	Intron 1 of 6	Prot: ENSP00000378488.2 UniProt:
	CYP1A1 ENST00000567032.5	TSL:1	c.-29-725C>A	intron	Intron 1 of 6	Prot: ENSP00000456585.1 UniProt:

CYP1A1 ENST00000379727.8

TSL:1MANE Select

HGVSc / HGVSpc.-29-725C>A

Exon rankIntron 1 of 6

intron

Prot: ENSP00000369050.3UniProt: P04798-1

CYP1A1 ENST00000395048.6

TSL:1

HGVSc / HGVSpc.-26-728C>A

Exon rankIntron 1 of 6

intron

Prot: ENSP00000378488.2UniProt: P04798-1

CYP1A1 ENST00000567032.5

TSL:1

HGVSc / HGVSpc.-29-725C>A

Exon rankIntron 1 of 6

intron

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 2 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:31
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:31

Showing 2 sources

Tested, but no data found:GnomAD4 exomeIf GnomAD4 is missing, the position is probably not covered by the project.

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Uncertain	12
BayesDel_noAF	Benign	-0.80
CADD	Benign	7.6
DANN	Benign	0.75
GPN-Star LLR	N/A	-0.14
GPN-Star score	N/A	0.14
PhyloP100	Benign	-0.27

Showing 7 of 7 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.040
SpliceAI score (max)	Benign	0.070	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: rs4646421;

hg19: chr15-75016192;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar