16-81264677-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_017429.3(BCO1):c.509C>T(p.Thr170Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0018 in 1,614,096 control chromosomes in the GnomAD database, including 4 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. T170T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0012 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0019 ( 4 hom. )

Consequence

BCO1
NM_017429.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts P:1U:3

Conservation

PhyloP100: 7.44

Publications

17 publications found

Variant links:

Genes affected

BCO1 (HGNC:13815): (beta-carotene oxygenase 1) Vitamin A metabolism is important for vital processes such as vision, embryonic development, cell differentiation, and membrane and skin protection. The protein encoded by this gene is a key enzyme in beta-carotene metabolism to vitamin A. It catalyzes the oxidative cleavage of beta,beta-carotene into two retinal molecules. [provided by RefSeq, Jul 2008]

BCO1 Gene-Disease associations (from GenCC):

hereditary hypercarotenemia and vitamin A deficiency
Inheritance: Unknown, AD Classification: SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet

BCO1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BS2

High AC in GnomAd4 at 181 Unknown,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BCO1	NM_017429.3 link	c.509C>T	p.Thr170Met	missense_variant	Exon 5 of 11	ENST00000258168.7	NP_059125.2	Q9HAY6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
BCO1	ENST00000258168.7 link	c.509C>T	p.Thr170Met	missense_variant	Exon 5 of 11	1	NM_017429.3	ENSP00000258168.2	Q9HAY6
BCO1	ENST00000563804.5 link	n.*133C>T		non_coding_transcript_exon_variant	Exon 4 of 10	2		ENSP00000457910.1	H3BV18
BCO1	ENST00000563804.5 link	n.*133C>T		3_prime_UTR_variant	Exon 4 of 10	2		ENSP00000457910.1	H3BV18

Frequencies

GnomAD3 genomes

AF:

0.00119

AC:

181

AN:

152166

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000459

Gnomad AMI

AF:

0.00220

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00160

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00207

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.00136

AC:

343

AN:

251486

AF XY:

0.00131

show subpopulations

Gnomad AFR exome

AF:

0.000431

Gnomad AMR exome

AF:

0.000202

Gnomad ASJ exome

AF:

0.000198

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00259

Gnomad NFE exome

AF:

0.00223

Gnomad OTH exome

AF:

0.00244

GnomAD4 exome

AF:

0.00186

AC:

2724

AN:

1461812

Hom.:

Cov.:

AF XY:

0.00175

AC XY:

1275

AN XY:

727212

show subpopulations

African (AFR)

AF:

0.000329

AC:

AN:

33476

American (AMR)

AF:

0.000201

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.000153

AC:

AN:

26134

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39698

South Asian (SAS)

AF:

0.0000348

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00223

AC:

119

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00225

AC:

2499

AN:

1111944

Other (OTH)

AF:

0.00129

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

150

301

451

602

752

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

188

282

376

470

<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:

0.00119

AC:

181

AN:

152284

Hom.:

Cov.:

AF XY:

0.00107

AC XY:

AN XY:

74462

show subpopulations

African (AFR)

AF:

0.000457

AC:

AN:

41544

American (AMR)

AF:

0.0000654

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5196

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00160

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00207

AC:

141

AN:

68032

Other (OTH)

AF:

0.000473

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00185

Hom.:

Bravo

AF:

0.00107

TwinsUK

AF:

0.00243

AC:

ALSPAC

AF:

0.00208

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00267

AC:

ExAC

AF:

0.00135

AC:

164

EpiCase

AF:

0.00196

EpiControl

AF:

0.00184

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hereditary hypercarotenemia and vitamin A deficiency

Pathogenic:1Uncertain:1

Aug 28, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

- -

Nov 01, 2007

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

not specified

Uncertain:1

May 04, 2022

Mendelics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

BCO1-related disorder

Uncertain:1

Oct 19, 2023

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The BCO1 c.509C>T variant is predicted to result in the amino acid substitution p.Thr170Met. This variant has previously been reported in the heterozygous state in a patient with hypercarotenemia and mild hypovitaminosis A (Lindqvist et al. 2007. PubMed ID: 17951468). Additionally, it was identified by exome sequencing in a patient with a connective tissue disorder and also yellow-orange skin (Meerschaut et al 2019. PubMed ID: 31595668). In in vitro studies, the p.Thr170Met substitution was reported to result in a 90% reduction in activity of the carotenoid 15,15’-monooxygenase enzyme (Lindqvist et al. 2007. PubMed ID: 17951468). A second variant was not identified in the reported patient’s BCO1 gene. The authors speculated that a single causative BCO1 variant could lead to a disease phenotype due to haploinsufficiency (Lindqvist et al. 2007. PubMed ID: 17951468). However, this variant is reported in 0.26% of alleles in individuals of European (Finnish) descent in gnomAD, including in one homozygous individual (http://gnomad.broadinstitute.org/variant/16-81298282-C-T), which is may be too common to be a primary cause of disease. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.52

BayesDel_addAF

Pathogenic

0.20

BayesDel_noAF

Pathogenic

0.51

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.94

Eigen

Pathogenic

0.85

Eigen_PC

Pathogenic

0.75

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.95

M_CAP

Pathogenic

0.56

MetaRNN

Uncertain

0.54

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.4

PhyloP100

7.4

PrimateAI

Benign

0.42

PROVEAN

Pathogenic

-5.6

REVEL

Pathogenic

0.94

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0020

Polyphen

1.0

Vest4

0.95

MVP

0.90

MPC

0.36

ClinPred

0.086

GERP RS

5.0

Varity_R

0.69

gMVP

0.85

Mutation Taster

=67/33

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.27

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.27

Position offset: -37

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over