rs1056827

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBA1

The NM_000104.4(CYP1B1):c.355G>T(p.Ala119Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.299 in 1,588,118 control chromosomes in the GnomAD database, including 73,925 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.35 ( 9842 hom., cov: 34)

Exomes 𝑓: 0.29 ( 64083 hom. )

Consequence

CYP1B1
NM_000104.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -0.503

Variant links:

Genes affected

CYP1B1 (HGNC:2597): (cytochrome P450 family 1 subfamily B member 1) This gene 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. The enzyme encoded by this gene localizes to the endoplasmic reticulum and metabolizes procarcinogens such as polycyclic aromatic hydrocarbons and 17beta-estradiol. Mutations in this gene have been associated with primary congenital glaucoma; therefore it is thought that the enzyme also metabolizes a signaling molecule involved in eye development, possibly a steroid. [provided by RefSeq, Jul 2008]

CYP1B1 links:

CYP1B1-AS1 (HGNC:28543): (CYP1B1 antisense RNA 1)

CYP1B1-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 35 curated pathogenic missense variants (we use a threshold of 10). The gene has 9 curated benign missense variants. Trascript score misZ: -2.0997 (below the threshold of 3.09). GenCC associations: The gene is linked to Peters anomaly, anterior segment dysgenesis 6, glaucoma 3A, congenital glaucoma, CYP1B1-related glaucoma with or without anterior segment dysgenesis.

BP4

Computational evidence support a benign effect (MetaRNN=1.7783786E-5).

BP6

Variant 2-38075034-C-A is Benign according to our data. Variant chr2-38075034-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 92437.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-38075034-C-A is described in Lovd as [Benign]. Variant chr2-38075034-C-A is described in Lovd as [Pathogenic].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.468 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP1B1	NM_000104.4 link	c.355G>T	p.Ala119Ser	missense_variant	Exon 2 of 3	ENST00000610745.5	NP_000095.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP1B1	ENST00000610745.5 link	c.355G>T	p.Ala119Ser	missense_variant	Exon 2 of 3	1	NM_000104.4	ENSP00000478561.1		Q16678

Frequencies

GnomAD3 genomes

AF:

0.348

AC:

52919

AN:

152028

Hom.:

9823

Cov.:

show subpopulations

Gnomad AFR

AF:

0.473

Gnomad AMI

AF:

0.502

Gnomad AMR

AF:

0.320

Gnomad ASJ

AF:

0.216

Gnomad EAS

AF:

0.182

Gnomad SAS

AF:

0.385

Gnomad FIN

AF:

0.365

Gnomad MID

AF:

0.346

Gnomad NFE

AF:

0.291

Gnomad OTH

AF:

0.317

GnomAD2 exomes

AF:

0.319

AC:

65208

AN:

204494

AF XY:

0.320

show subpopulations

Gnomad AFR exome

AF:

0.490

Gnomad AMR exome

AF:

0.317

Gnomad ASJ exome

AF:

0.234

Gnomad EAS exome

AF:

0.196

Gnomad FIN exome

AF:

0.366

Gnomad NFE exome

AF:

0.303

Gnomad OTH exome

AF:

0.310

GnomAD4 exome

AF:

0.294

AC:

422171

AN:

1435970

Hom.:

64083

Cov.:

AF XY:

0.296

AC XY:

211668

AN XY:

713932

show subpopulations

Gnomad4 AFR exome

AF:

0.489

AC:

16279

AN:

33274

Gnomad4 AMR exome

AF:

0.314

AC:

13665

AN:

43542

Gnomad4 ASJ exome

AF:

0.231

AC:

5992

AN:

25914

Gnomad4 EAS exome

AF:

0.150

AC:

5849

AN:

39110

Gnomad4 SAS exome

AF:

0.376

AC:

31936

AN:

84858

Gnomad4 FIN exome

AF:

0.360

AC:

13169

AN:

36604

Gnomad4 NFE exome

AF:

0.285

AC:

315320

AN:

1107158

Gnomad4 Remaining exome

AF:

0.301

AC:

17993

AN:

59794

Heterozygous variant carriers

21084

42169

63253

84338

105422

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Exome Hom

Variant carriers

10544

21088

31632

42176

52720

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.348

AC:

52986

AN:

152148

Hom.:

9842

Cov.:

AF XY:

0.352

AC XY:

26171

AN XY:

74386

show subpopulations

Gnomad4 AFR

AF:

0.474

AC:

0.473513

AN:

0.473513

Gnomad4 AMR

AF:

0.320

AC:

0.319579

AN:

0.319579

Gnomad4 ASJ

AF:

0.216

AC:

0.216138

AN:

0.216138

Gnomad4 EAS

AF:

0.182

AC:

0.181765

AN:

0.181765

Gnomad4 SAS

AF:

0.385

AC:

0.385253

AN:

0.385253

Gnomad4 FIN

AF:

0.365

AC:

0.364794

AN:

0.364794

Gnomad4 NFE

AF:

0.291

AC:

0.291166

AN:

0.291166

Gnomad4 OTH

AF:

0.323

AC:

0.323084

AN:

0.323084

Heterozygous variant carriers

1779

3558

5338

7117

8896

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Genome Hom

Variant carriers

512

1024

1536

2048

2560

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.298

Hom.:

5969

Bravo

AF:

0.345

TwinsUK

AF:

0.259

AC:

960

ALSPAC

AF:

0.280

AC:

1080

ESP6500AA

AF:

0.452

AC:

1833

ESP6500EA

AF:

0.278

AC:

2239

ExAC

AF:

0.305

AC:

35266

Asia WGS

AF:

0.313

AC:

1089

AN:

3476

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Dec 03, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 14, 2013

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Glaucoma 3A

Benign:2

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Jul 30, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 26681220, 25619313, 26283052, 10739169, 18575334, 23861929, 18573508, 11854439, 22177211, 19820397, 24591815, 19383894, 15958554) -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Anterior segment dysgenesis 6

Benign:1

Jul 30, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Glaucoma 3, primary infantile, B;C1856439:Glaucoma 3A;C4310623:Anterior segment dysgenesis 6

Benign:1

Apr 28, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Congenital glaucoma

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.081

BayesDel_addAF

Benign

-0.79

BayesDel_noAF

Benign

-0.77

CADD

Benign

4.7

DANN

Benign

0.83

DEOGEN2

Benign

0.069

T;T;.

Eigen

Benign

-1.8

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.20

LIST_S2

Benign

0.34

.;T;T

MetaRNN

Benign

0.000018

T;T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

-0.55

N;N;.

PrimateAI

Benign

0.28

Sift4G

Benign

0.16

T;T;.

Vest4

0.022

ClinPred

0.000019

GERP RS

-0.88

Varity_R

0.053

gMVP

0.59

Mutation Taster

=99/1

polymorphism (auto)

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

LitVar

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

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over