15-74720496-C-T

Variant names:

• chr15-74720496-C-T
• rs56343424
• NM_001319217.2:c.1532G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001319217.2(CYP1A1):​c.1532G>A​(p.Arg511His) variant causes a missense change. The variant allele was found at a frequency of 0.0000134 in 1,565,894 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R511L) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: CYP1A1 NM_001319217.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.29
• Publications: 7 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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP1A1	NM_001319217.2	MANE Select	c.1532G>A	p.Arg511His	missense	Exon 7 of 7	NP_001306146.1	P04798-1
	CYP1A1	NM_000499.5		c.1532G>A	p.Arg511His	missense	Exon 7 of 7	NP_000490.1	A0N0X8
	CYP1A1	NM_001319216.2		c.1445G>A	p.Arg482His	missense	Exon 6 of 6	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.1532G>A	p.Arg511His	missense	Exon 7 of 7	ENSP00000369050.3	P04798-1
	CYP1A1	ENST00000395048.6	TSL:1	c.1532G>A	p.Arg511His	missense	Exon 7 of 7	ENSP00000378488.2	P04798-1
	CYP1A1	ENST00000567032.5	TSL:1	c.1532G>A	p.Arg511His	missense	Exon 7 of 7	ENSP00000456585.1	P04798-1

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152162 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

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: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000331 AC: 7 AN: 211494 AF XY: 0.0000179

Gnomad AFR exome AF: 0.000126

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000224

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000103

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000113 AC: 16 AN: 1413732 Hom.: 0 Cov.: 30 AF XY: 0.00000860 AC XY: 6 AN XY: 697758

African (AFR) AF: 0.0000923 AC: 3 AN: 32514

American (AMR) AF: 0.0000255 AC: 1 AN: 39146

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22444

East Asian (EAS) AF: 0.000127 AC: 5 AN: 39354

South Asian (SAS) AF: 0.0000130 AC: 1 AN: 77020

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51292

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5516

European-Non Finnish (NFE) AF: 0.00000551 AC: 6 AN: 1088042

Other (OTH) AF: 0.00 AC: 0 AN: 58404

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152162 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74326

African (AFR) AF: 0.0000724 AC: 3 AN: 41430

American (AMR) AF: 0.00 AC: 0 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 1

Bravo AF: 0.0000302

ESP6500AA AF: 0.000228 AC: 1

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000331 AC: 4

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Pathogenic	0.18
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.077	T
Eigen	Pathogenic	0.72
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.68	T
M_CAP	Benign	0.070	D
MetaRNN	Uncertain	0.53	D
MetaSVM	Uncertain	0.46	D
MutationAssessor	Pathogenic	3.5	M
PhyloP100		6.3
PrimateAI	Benign	0.38	T
PROVEAN	Uncertain	-2.6	D
REVEL	Uncertain	0.58
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.42
MVP		1.0
MPC		0.24
ClinPred		0.91	D
GERP RS		5.7
Varity_R		0.39
gMVP		0.80
Mutation Taster		=82/18	polymorphism

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

Other links and lift over

dbSNP: rs56343424; hg19: chr15-75012837; COSMIC: COSV101122286; COSMIC: COSV101122286;