rs141781255

Positions:

• chr16-81290555-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_017429.3(BCO1):​c.1622G>A​(p.Cys541Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00654 in 1,613,678 control chromosomes in the GnomAD database, including 63 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0062 (6 hom., cov: 33)
  • Exomes 𝑓: 0.0066 (57 hom.)
• Consequence: BCO1 NM_017429.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -0.928

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]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0053551495).
• BP6: Variant 16-81290555-G-A is Benign according to our data. Variant chr16-81290555-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 377022.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.00657 (9601/1461428) while in subpopulation SAS AF= 0.0158 (1366/86258). AF 95% confidence interval is 0.0151. There are 57 homozygotes in gnomad4_exome. There are 5034 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 950 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BCO1	NM_017429.3	c.1622G>A	p.Cys541Tyr	missense_variant	11/11	ENST00000258168.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BCO1	ENST00000258168.7	c.1622G>A	p.Cys541Tyr	missense_variant	11/11	1	NM_017429.3	P1
BCO1	ENST00000563804.5	c.*1246G>A		3_prime_UTR_variant, NMD_transcript_variant	10/10	2

Frequencies

GnomAD3 genomes AF: 0.00623 AC: 948 AN: 152132 Hom.: 6 Cov.: 33

Gnomad AFR AF: 0.00101

Gnomad AMI AF: 0.0296

Gnomad AMR AF: 0.00576

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0110

Gnomad FIN AF: 0.0143

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00816

Gnomad OTH AF: 0.00720

GnomAD3 exomes AF: 0.00715 AC: 1795 AN: 250954 Hom.: 18 AF XY: 0.00775 AC XY: 1052 AN XY: 135676

Gnomad AFR exome AF: 0.000800

Gnomad AMR exome AF: 0.00231

Gnomad ASJ exome AF: 0.00506

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0168

Gnomad FIN exome AF: 0.0135

Gnomad NFE exome AF: 0.00696

Gnomad OTH exome AF: 0.00962

GnomAD4 exome AF: 0.00657 AC: 9601 AN: 1461428 Hom.: 57 Cov.: 31 AF XY: 0.00692 AC XY: 5034 AN XY: 727056

Gnomad4 AFR exome AF: 0.000717

Gnomad4 AMR exome AF: 0.00315

Gnomad4 ASJ exome AF: 0.00513

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0158

Gnomad4 FIN exome AF: 0.0130

Gnomad4 NFE exome AF: 0.00612

Gnomad4 OTH exome AF: 0.00641

GnomAD4 genome AF: 0.00624 AC: 950 AN: 152250 Hom.: 6 Cov.: 33 AF XY: 0.00654 AC XY: 487 AN XY: 74446

Gnomad4 AFR AF: 0.00101

Gnomad4 AMR AF: 0.00575

Gnomad4 ASJ AF: 0.00461

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0114

Gnomad4 FIN AF: 0.0143

Gnomad4 NFE AF: 0.00816

Gnomad4 OTH AF: 0.00712

Alfa AF: 0.00635 Hom.: 13

Bravo AF: 0.00496

TwinsUK AF: 0.00485 AC: 18

ALSPAC AF: 0.00337 AC: 13

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.00570 AC: 49

ExAC AF: 0.00743 AC: 902

Asia WGS AF: 0.00462 AC: 17 AN: 3478

EpiCase AF: 0.00703

EpiControl AF: 0.00735

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 31, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Feb 13, 2017	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	0.17
DANN	Benign	0.77
DEOGEN2	Benign	0.18	T
Eigen	Benign	-0.96
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.021	N
LIST_S2	Benign	0.42	T
MetaRNN	Benign	0.0054	T
MetaSVM	Benign	-0.34	T
MutationAssessor	Benign	1.8	L
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.79	N
REVEL	Benign	0.20
Sift	Uncertain	0.0020	D
Sift4G	Benign	0.089	T
Polyphen		0.047	B
Vest4		0.16
MVP		0.55
MPC		0.094
ClinPred		0.0088	T
GERP RS		-1.4
Varity_R		0.33
gMVP		0.35

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

Other links and lift over

dbSNP: rs141781255; hg19: chr16-81324160; COSMIC: COSV99079102;