dbSNP rs28399429: CYP1A1:p.Val482Leu (chr15-74720584-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001319217.2(CYP1A1):c.1444G>T(p.Val482Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,438 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V482M) has been classified as Benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

CYP1A1
NM_001319217.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.00800

Publications

0 publications found

Variant links:

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]

CYP1A1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.09109777).

Variant Effect in Transcripts

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

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CYP1A1	NM_001319217.2	MANE Select	c.1444G>T	p.Val482Leu	missense	Exon 7 of 7	NP_001306146.1	P04798-1
CYP1A1	NM_000499.5		c.1444G>T	p.Val482Leu	missense	Exon 7 of 7	NP_000490.1	A0N0X8
CYP1A1	NM_001319216.2		c.1357G>T	p.Val453Leu	missense	Exon 6 of 6	NP_001306145.1	E7EMT5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CYP1A1	ENST00000379727.8	TSL:1 MANE Select	c.1444G>T	p.Val482Leu	missense	Exon 7 of 7	ENSP00000369050.3	P04798-1
CYP1A1	ENST00000395048.6	TSL:1	c.1444G>T	p.Val482Leu	missense	Exon 7 of 7	ENSP00000378488.2	P04798-1
CYP1A1	ENST00000567032.5	TSL:1	c.1444G>T	p.Val482Leu	missense	Exon 7 of 7	ENSP00000456585.1	P04798-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461438

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726990

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44668

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26076

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86172

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53398

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111804

Other (OTH)

AF:

0.0000166

AC:

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.58

CADD

Benign

4.6

(source)

DANN

Benign

0.81

DEOGEN2

Benign

0.019

Eigen

Benign

-0.83

Eigen_PC

Benign

-0.81

FATHMM_MKL

Benign

0.37

LIST_S2

Benign

0.64

M_CAP

Benign

0.017

MetaRNN

Benign

0.091

MetaSVM

Benign

-0.96

MutationAssessor

Benign

0.66

PhyloP100

-0.0080

PrimateAI

Benign

0.34

PROVEAN

Benign

-0.90

REVEL

Benign

0.026

Sift

Benign

0.31

Sift4G

Benign

0.28

Polyphen

0.053

Vest4

0.077

MutPred

0.28

Loss of ubiquitination at K487 (P = 0.1062)

MVP

0.60

MPC

0.031

ClinPred

0.17

GERP RS

3.7

Varity_R

0.22

gMVP

0.38

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over