rs4646421

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr15-74723851-G-A
• chr15-74723851-G-C
• chr15-74723851-G-T

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.-29-725C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.215 (AC=32,708) in the gnomAD database across 152,078 control chromosomes, including 4,844 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.395. 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: 𝑓 0.22 (4844 hom., cov: 31)
• Consequence: CYP1A1 NM_001319217.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.265
• Publications: 69 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); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Strong).
	BA1Stand-alone benign allele frequency (>5%)		GnomAD effective popmax AF >5% — BA1 stand-alone benign; GnomAD reliable popmax AF = 0.3954 — 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.-29-725C>T		intron	N/A	NP_001306146.1	A0N0X8
	CYP1A1	NM_000499.5		c.-26-728C>T		intron	N/A	NP_000490.1	A0N0X8
	CYP1A1	NM_001319216.2		c.-29-725C>T		intron	N/A	NP_001306145.1	E7EMT5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP1A1	ENST00000379727.8	TSL:1 MANE Select	c.-29-725C>T		intron	N/A	ENSP00000369050.3	P04798-1
	CYP1A1	ENST00000395048.6	TSL:1	c.-26-728C>T		intron	N/A	ENSP00000378488.2	P04798-1
	CYP1A1	ENST00000567032.5	TSL:1	c.-29-725C>T		intron	N/A	ENSP00000456585.1	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: 0.215	AC:32628	Hom:4823	AN:151960	Cov:31
GnomAD4 genome	AF: 0.215	AC:32708	Hom:4844	AN:152078	Cov:31
TOPMed (Bravo)	AF: 0.236	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.145	AC:45174	Hom:4868	AN:310600	Cov:
Local & regional cohorts 10 sources Population-specific and national genomic databases
ABraOM SABE-WGS-1171	AF: 0.226	AC:530	Hom:74	AN:2342	Cov:
ChinaMAP Phase 1	AF: 0.409	AC:	Hom:	AN:	Cov:
Denmark Genome	AF: 0.110	AC:33	Hom:	AN:300	Cov:
GenomeAsia100K	AF: 0.419	AC:1452	Hom:	AN:3478	Cov:
Korea4K (4,157 Koreans)	AF: 0.384	AC:2775	Hom:	AN:7232	Cov:
Qatari Genome	AF: 0.142	AC:25	Hom:	AN:176	Cov:
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.366	AC:44822	Hom:8280	AN:122618	Cov:
Turkish Variome	AF: 0.155	AC:239	Hom:23	AN:1546	Cov:
UK10K	AF: 0.106	AC:805	Hom:	AN:7562	Cov:
WBBC (Westlake BioBank for Chinese) pilot	AF: 0.416	AC:3729	Hom:755	AN:8960	Cov:

Showing 14 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	11
BayesDel_noAF	Benign	-0.78
CADD	Benign	4.9
DANN	Benign	0.68
GPN-Star LLR	N/A	-0.36
GPN-Star score	N/A	0.36
Mutation Taster	N/A	100/0	polymorphism (auto)
PhyloP100	Benign	-0.27

Showing 8 of 8 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
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.

Other links and lift over

dbSNP: rs4646421;

hg19: chr15-75016192;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar