15-74721022-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001319217.2(CYP1A1):ā€‹c.1198T>Cā€‹(p.Tyr400His) variant causes a missense change. The variant allele was found at a frequency of 0.0000607 in 1,614,074 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: š‘“ 0.000033 ( 0 hom., cov: 32)
Exomes š‘“: 0.000064 ( 0 hom. )

Consequence

CYP1A1
NM_001319217.2 missense

Scores

5
14

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.16
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
CYP1A1NM_001319217.2 linkuse as main transcriptc.1198T>C p.Tyr400His missense_variant 6/7 ENST00000379727.8
CYP1A1NM_000499.5 linkuse as main transcriptc.1198T>C p.Tyr400His missense_variant 6/7
CYP1A1NM_001319216.2 linkuse as main transcriptc.1166+177T>C intron_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
CYP1A1ENST00000379727.8 linkuse as main transcriptc.1198T>C p.Tyr400His missense_variant 6/71 NM_001319217.2 P1P04798-1

Frequencies

GnomAD3 genomes
AF:
0.0000328
AC:
5
AN:
152208
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000735
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000239
AC:
6
AN:
251476
Hom.:
0
AF XY:
0.0000294
AC XY:
4
AN XY:
135910
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000440
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.0000636
AC:
93
AN:
1461866
Hom.:
0
Cov.:
32
AF XY:
0.0000633
AC XY:
46
AN XY:
727238
show subpopulations
Gnomad4 AFR exome
AF:
0.0000597
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000782
Gnomad4 OTH exome
AF:
0.0000662
GnomAD4 genome
AF:
0.0000328
AC:
5
AN:
152208
Hom.:
0
Cov.:
32
AF XY:
0.0000403
AC XY:
3
AN XY:
74358
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000735
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000965
Hom.:
0
Bravo
AF:
0.0000416

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsApr 25, 2023The c.1198T>C (p.Y400H) alteration is located in exon 6 (coding exon 5) of the CYP1A1 gene. This alteration results from a T to C substitution at nucleotide position 1198, causing the tyrosine (Y) at amino acid position 400 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.097
BayesDel_addAF
Benign
-0.13
T
BayesDel_noAF
Benign
-0.29
CADD
Benign
23
DANN
Benign
0.95
DEOGEN2
Benign
0.069
T;T;T;T;.;T
Eigen
Benign
-0.042
Eigen_PC
Benign
0.030
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Benign
0.77
T;T;.;.;T;T
M_CAP
Benign
0.065
D
MetaRNN
Uncertain
0.53
D;D;D;D;D;D
MetaSVM
Benign
-0.44
T
MutationAssessor
Benign
1.5
.;L;L;L;.;.
MutationTaster
Benign
1.0
D;D;D;D;D
PrimateAI
Uncertain
0.50
T
PROVEAN
Uncertain
-3.4
.;D;D;D;D;D
REVEL
Uncertain
0.40
Sift
Benign
0.33
.;T;T;T;T;T
Sift4G
Benign
0.20
T;T;T;T;T;T
Polyphen
0.18
.;B;B;B;.;.
Vest4
0.40
MVP
0.89
MPC
0.16
ClinPred
0.52
D
GERP RS
4.0
Varity_R
0.67
gMVP
0.68

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1008131147; hg19: chr15-75013363; API