16-81262175-C-A

Variant names:

• chr16-81262175-C-A
• rs35683292
• NM_017429.3:c.363C>A

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 1P and 16B. PP3 BP6_Very_Strong BA1

The NM_017429.3(BCO1):​c.363C>A​(p.Thr121Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0504 in 1,613,826 control chromosomes in the GnomAD database, including 2,423 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.036 (150 hom., cov: 31)
  • Exomes 𝑓: 0.052 (2273 hom.)
• Consequence: BCO1 NM_017429.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.45
• Publications: 7 publications found

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

ENSG00000280182 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -15 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• BP6: Variant 16-81262175-C-A is Benign according to our data. Variant chr16-81262175-C-A is described in ClinVar as Benign. ClinVar VariationId is 1230730.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0562 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017429.3. 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
	BCO1	NM_017429.3	MANE Select	c.363C>A	p.Thr121Thr	synonymous	Exon 4 of 11	NP_059125.2	Q9HAY6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BCO1	ENST00000258168.7	TSL:1 MANE Select	c.363C>A	p.Thr121Thr	synonymous	Exon 4 of 11	ENSP00000258168.2	Q9HAY6
	BCO1	ENST00000891666.1		c.363C>A	p.Thr121Thr	synonymous	Exon 4 of 9	ENSP00000561725.1
	BCO1	ENST00000891665.1		c.363C>A	p.Thr121Thr	synonymous	Exon 4 of 9	ENSP00000561724.1

Frequencies

GnomAD3 genomes AF: 0.0364 AC: 5532 AN: 152124 Hom.: 150 Cov.: 31

Gnomad AFR AF: 0.0110

Gnomad AMI AF: 0.0956

Gnomad AMR AF: 0.0250

Gnomad ASJ AF: 0.0144

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0168

Gnomad FIN AF: 0.0457

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0577

Gnomad OTH AF: 0.0292

GnomAD2 exomes AF: 0.0355 AC: 8922 AN: 251414 AF XY: 0.0361

Gnomad AFR exome AF: 0.00941

Gnomad AMR exome AF: 0.0156

Gnomad ASJ exome AF: 0.0146

Gnomad EAS exome AF: 0.000163

Gnomad FIN exome AF: 0.0438

Gnomad NFE exome AF: 0.0557

Gnomad OTH exome AF: 0.0318

GnomAD4 exome AF: 0.0519 AC: 75811 AN: 1461584 Hom.: 2273 Cov.: 30 AF XY: 0.0516 AC XY: 37486 AN XY: 727084

African (AFR) AF: 0.00747 AC: 250 AN: 33472

American (AMR) AF: 0.0168 AC: 751 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0149 AC: 390 AN: 26136

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39696

South Asian (SAS) AF: 0.0224 AC: 1930 AN: 86256

European-Finnish (FIN) AF: 0.0451 AC: 2405 AN: 53338

Middle Eastern (MID) AF: 0.0104 AC: 60 AN: 5766

European-Non Finnish (NFE) AF: 0.0607 AC: 67500 AN: 1111808

Other (OTH) AF: 0.0418 AC: 2522 AN: 60390

GnomAD4 genome AF: 0.0363 AC: 5531 AN: 152242 Hom.: 150 Cov.: 31 AF XY: 0.0354 AC XY: 2635 AN XY: 74432

African (AFR) AF: 0.0110 AC: 457 AN: 41550

American (AMR) AF: 0.0250 AC: 382 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.0144 AC: 50 AN: 3472

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5182

South Asian (SAS) AF: 0.0164 AC: 79 AN: 4816

European-Finnish (FIN) AF: 0.0457 AC: 485 AN: 10606

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0577 AC: 3927 AN: 68024

Other (OTH) AF: 0.0289 AC: 61 AN: 2114

Alfa AF: 0.0400 Hom.: 99

Bravo AF: 0.0326

Asia WGS AF: 0.00808 AC: 28 AN: 3478

EpiCase AF: 0.0519

EpiControl AF: 0.0521

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	BCO1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_noAF	Benign	-0.67
CADD	Benign	13
DANN	Benign	0.53
PhyloP100		-1.5
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.67		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.67		Position offset: 2

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

Other links and lift over

dbSNP: rs35683292; hg19: chr16-81295780;