15-74720645-GGT-AGA

Variant names:

• chr15-74720645-GGT-AGA
• NM_001319217.2:c.1381_1383delACCinsTCT
• CYP1A1 p.Thr461Ser

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+2 Uncertain · Warm

-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). PM2

The NM_001319217.2(CYP1A1):c.1381_1383delACCinsTCT (p.Thr461Ser) variant causes a missense change. Note: allele frequency estimates from gnomAD may be inaccurate for this variant type (MNP or indel longer than 3 bp) due to technology limitations. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.T461N: Benign (ClinVar VariationId 3056253, 0 stars)

• Frequency: Genomes: not found (cov: 32)
• Consequence: CYP1A1 NM_001319217.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.42
• Publications: 0 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: Uncertain_significance. 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.

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.1381_1383delACCinsTCT p.Thr461Ser	missense	N/A	Prot: NP_001306146.1 UniProt:
	CYP1A1 NM_000499.5		c.1381_1383delACCinsTCT p.Thr461Ser	missense	N/A	Prot: NP_000490.1 UniProt:
	CYP1A1 NM_001319216.2		c.1294_1296delACCinsTCT p.Thr432Ser	missense	N/A	Prot: NP_001306145.1 UniProt:

CYP1A1 NM_001319217.2

MANE Select

HGVSc / HGVSpc.1381_1383delACCinsTCTp.Thr461Ser

Exon rankN/A

missense

Prot: NP_001306146.1UniProt: A0N0X8P04798-1

CYP1A1 NM_000499.5

HGVSc / HGVSpc.1381_1383delACCinsTCTp.Thr461Ser

Exon rankN/A

missense

Prot: NP_000490.1UniProt: A0N0X8P04798-1

CYP1A1 NM_001319216.2

HGVSc / HGVSpc.1294_1296delACCinsTCTp.Thr432Ser

Exon rankN/A

missense

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.1381_1383delACCinsTCT p.Thr461Ser	missense	N/A	Prot: ENSP00000369050.3 UniProt:
	CYP1A1 ENST00000395048.6	TSL:1	c.1381_1383delACCinsTCT p.Thr461Ser	missense	N/A	Prot: ENSP00000378488.2 UniProt:
	CYP1A1 ENST00000567032.5	TSL:1	c.1381_1383delACCinsTCT p.Thr461Ser	missense	N/A	Prot: ENSP00000456585.1 UniProt:

CYP1A1 ENST00000379727.8

TSL:1MANE Select

HGVSc / HGVSpc.1381_1383delACCinsTCTp.Thr461Ser

Exon rankN/A

missense

Prot: ENSP00000369050.3UniProt: P04798-1

CYP1A1 ENST00000395048.6

TSL:1

HGVSc / HGVSpc.1381_1383delACCinsTCTp.Thr461Ser

Exon rankN/A

missense

Prot: ENSP00000378488.2UniProt: P04798-1

CYP1A1 ENST00000567032.5

TSL:1

HGVSc / HGVSpc.1381_1383delACCinsTCTp.Thr461Ser

Exon rankN/A

missense

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:32
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32

Showing 2 sources

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
PhyloP100	Benign	1.4

Showing 1 of 1 scores

Splicing Scores

No splicing scores have been computed for this variant.

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

hg19: chr15-75012986;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar