rs9282671

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_000104.4(CYP1B1):c.241T>A(p.Tyr81Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00391 in 1,574,856 control chromosomes in the GnomAD database, including 28 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. Y81Y) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0035 ( 3 hom., cov: 34)

Exomes 𝑓: 0.0040 ( 25 hom. )

Consequence

CYP1B1
NM_000104.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:5B:3

Conservation

PhyloP100: 5.07

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 made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.010914177).

BS2

High Homozygotes in GnomAd at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYP1B1	NM_000104.4 linkuse as main transcript	c.241T>A	p.Tyr81Asn	missense_variant	2/3	ENST00000610745.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP1B1	ENST00000610745.5 linkuse as main transcript	c.241T>A	p.Tyr81Asn	missense_variant	2/3	1	NM_000104.4	P1

Frequencies

GnomAD3 genomes

AF:

0.00349

AC:

531

AN:

152176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000845

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00118

Gnomad ASJ

AF:

0.00230

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00248

Gnomad FIN

AF:

0.0136

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00456

Gnomad OTH

AF:

0.00144

GnomAD3 exomes

AF:

0.00355

AC:

654

AN:

183970

Hom.:

AF XY:

0.00381

AC XY:

389

AN XY:

101966

show subpopulations

Gnomad AFR exome

AF:

0.000879

Gnomad AMR exome

AF:

0.00214

Gnomad ASJ exome

AF:

0.00113

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00298

Gnomad FIN exome

AF:

0.0131

Gnomad NFE exome

AF:

0.00451

Gnomad OTH exome

AF:

0.00428

GnomAD4 exome

AF:

0.00395

AC:

5622

AN:

1422562

Hom.:

Cov.:

AF XY:

0.00391

AC XY:

2757

AN XY:

705698

show subpopulations

Gnomad4 AFR exome

AF:

0.000726

Gnomad4 AMR exome

AF:

0.00188

Gnomad4 ASJ exome

AF:

0.00144

Gnomad4 EAS exome

AF:

0.0000260

Gnomad4 SAS exome

AF:

0.00277

Gnomad4 FIN exome

AF:

0.0146

Gnomad4 NFE exome

AF:

0.00408

Gnomad4 OTH exome

AF:

0.00388

GnomAD4 genome

AF:

0.00348

AC:

530

AN:

152294

Hom.:

Cov.:

AF XY:

0.00399

AC XY:

297

AN XY:

74480

show subpopulations

Gnomad4 AFR

AF:

0.000842

Gnomad4 AMR

AF:

0.00118

Gnomad4 ASJ

AF:

0.00230

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00228

Gnomad4 FIN

AF:

0.0136

Gnomad4 NFE

AF:

0.00456

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00405

Hom.:

Bravo

AF:

0.00250

TwinsUK

AF:

0.00297

AC:

ALSPAC

AF:

0.00415

AC:

ESP6500AA

AF:

0.000729

AC:

ESP6500EA

AF:

0.00411

AC:

ExAC

AF:

0.00345

AC:

403

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:5Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2023	CYP1B1: PM3, PM2:Supporting, PS3:Supporting -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Nov 30, 2021	Identified in patients with primary congenital glaucoma, primary open-angle glaucoma, coloboma and micropthalmia, but many of these patients were not observed to harbor a second variant in CYP1B1, and Y81N did not segregate with disease in some families. (Melki et al., 2004; Mill et al., 2013; Prokudin et al., 2014; Reis et al., 2016; Rauf et al., 2016); Published functional studies demonstrate a reduction in enzyme activity compared to the wild type (Choudhary et al., 2008; Banerjee et al., 2016); This variant is associated with the following publications: (PMID: 19793111, 27508083, 22004014, 19204079, 19643970, 19234632, 27243976, 27820421, 25646030, 27777502, 23922489, 24281366, 16862072, 18470941, 15342693, 18622259) -

Primary open angle glaucoma

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 01, 2008

- -

Anterior segment dysgenesis

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Jun 11, 2020

Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as a VUS - 3A. 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0106 - This gene is known to be associated with autosomal recessive disease. (N) 0112 - Variants in this gene are known to have reduced penetrance (PMID: 26550445, PMID: 10655546). (N) 0200 - Variant is predicted to result in a missense amino acid change from tyrosine to asparagine (exon 2). (N) 0251 - Variant is heterozygous. (N) 0305 - Variant is present in gnomAD >=0.01 and <0.03 for a recessive condition (772 heterozygotes, 9 homozygotes). (N) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (2 heterozygotes, 0 homozygotes). (N) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (P) 0600 - Variant is located in an annotated domain or motif, (p450 cytochrome domain; PDB, NCBI). (N) 0705 - No comparable variants have previous evidence for pathogenicity. (N) 0808 - Previous reports of pathogenicity are conflicting. This variant has been reported as a VUS and benign, and observed in heterozygote controls or carriers with primary open-angle glaucoma (POAG) (ClinVar, LOVD, PMID: 27777502, PMID: 15342693). However more recently, this variant has been reported as pathogenic in homozygous and compound heterozygous patients with POAG and congenital glaucoma (PMID: 24281366, PMID: 27508083, PMID: 30520782, PMID: 22004014). (N) 1002 - Moderate functional evidence supporting abnormal protein function. Transfected cells demonstrated reduced protein expression (PMID: 18470941). (P) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign -

Irido-corneo-trabecular dysgenesis

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 2017

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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Congenital ocular coloboma

Uncertain:1

Uncertain significance, no assertion criteria provided

research

Eye Genetics Research Group, Children's Medical Research Institute

Mar 30, 2012

- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Aug 14, 2013

- -

Glaucoma 3A

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 2017

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 determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Congenital glaucoma

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 30, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.62

BayesDel_addAF

Benign

-0.035

BayesDel_noAF

Pathogenic

0.18

Cadd

Pathogenic

Dann

Uncertain

0.99

DEOGEN2

Uncertain

0.72

D;D;.

Eigen

Pathogenic

0.79

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Pathogenic

0.98

MetaRNN

Benign

0.011

T;T;T

MetaSVM

Uncertain

0.49

MutationAssessor

Pathogenic

4.3

H;H;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.68

Sift4G

Pathogenic

0.0

D;D;.

Vest4

0.88

MVP

0.53

ClinPred

0.093

GERP RS

4.4

Varity_R

0.84

gMVP

0.93

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