rs80338851
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_194318.4(B3GLCT):c.660+1G>A variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00103 in 1,588,686 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Genomes: 𝑓 0.00080 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0011 ( 0 hom. )
Consequence
B3GLCT
NM_194318.4 splice_donor, intron
NM_194318.4 splice_donor, intron
Scores
4
2
1
Splicing: ADA: 1.000
2
Clinical Significance
Conservation
PhyloP100: 8.71
Genes affected
B3GLCT (HGNC:20207): (beta 3-glucosyltransferase) The protein encoded by this gene is a beta-1,3-glucosyltransferase that transfers glucose to O-linked fucosylglycans on thrombospondin type-1 repeats (TSRs) of several proteins. The encoded protein is a type II membrane protein. Defects in this gene are a cause of Peters-plus syndrome (PPS).[provided by RefSeq, Mar 2009]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 13-31269278-G-A is Pathogenic according to our data. Variant chr13-31269278-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 1264.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-31269278-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| B3GLCT | NM_194318.4 | c.660+1G>A | splice_donor_variant, intron_variant | ENST00000343307.5 | NP_919299.3 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| B3GLCT | ENST00000343307.5 | c.660+1G>A | splice_donor_variant, intron_variant | 1 | NM_194318.4 | ENSP00000343002.4 | ||||
| B3GLCT | ENST00000461652.2 | n.275+1G>A | splice_donor_variant, intron_variant | 3 |
Frequencies
GnomAD3 genomes 0.000802 AC: 122AN: 152076Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000700 AC: 175AN: 250126Hom.: 0 AF XY: 0.000688 AC XY: 93AN XY: 135206
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GnomAD4 exome AF: 0.00106 AC: 1521AN: 1436492Hom.: 0 Cov.: 27 AF XY: 0.00101 AC XY: 721AN XY: 716300
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GnomAD4 genome 0.000802 AC: 122AN: 152194Hom.: 0 Cov.: 32 AF XY: 0.000632 AC XY: 47AN XY: 74420
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:26Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Peters plus syndrome Pathogenic:15Other:1
| Pathogenic, criteria provided, single submitter | clinical testing | Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center | Jan 25, 2023 | PVS1, PM3_strong - |
| Pathogenic, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Mar 08, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein | Jan 23, 2023 | ACMG classification criteria: PVS1 strong, PM3 strong - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 22, 2023 | This sequence change affects a donor splice site in intron 8 of the B3GLCT gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in B3GLCT are known to be pathogenic (PMID: 18798333, 23889335). This variant is present in population databases (rs80338851, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. Disruption of this splice site has been observed in individuals with Peters-Plus syndrome (PMID: 16909395, 18199743, 19796186, 23161355, 23213277, 23889335, 26684045). ClinVar contains an entry for this variant (Variation ID: 1264). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | 3billion | May 22, 2022 | Substitution at the splicing junction produces an abnormal splicing effect, which is expected to cause a loss of normal protein function via nonsense-mediated mRNA decay. This variant has been reported as pathogenic more than twice (ClinVar ID: VCV000001264), along with assertion criteria based on the ACMG guidelines. It has been reported with an extremely low frequency in the gnomAD v2.1.1 (https://gnomad.broadinstitute.org/) dataset. Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Equipe Genetique des Anomalies du Developpement, Université de Bourgogne | Apr 12, 2016 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics Laboratory, University Hospital Schleswig-Holstein | Mar 01, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jan 06, 2023 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Knight Diagnostic Laboratories, Oregon Health and Sciences University | Nov 10, 2017 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | The B3GALTL c.660+1G>A variant occurs in a canonical splice site (donor) and is therefore predicted to disrupt or distort the normal gene product. The c.660+1G>A variant is well described in the literature and is the most frequently identified variant in individuals with Peters plus syndrome (PPS) (Saskia et al. 2014). Across a selection of literature, the c.660+1G>A variant was reported in a homozygous state in 24 patients and in a compound heterozygous state in 13 patients (Lesnik Oberstein et al. 2006; Reis et al. 2008; Dassie-Ajdid et al. 2009; Schoner et al. 2013; Weh et al. 2013). Parental testing was described in at least 15 sets of parent of affected patients, and the c.660+1G>A variant was identified in unaffected parents as expected based on their child's genotype. Hess et al.(2008) demonstrated that synthesis of the disaccharide Glc-β1,3-Fuc-O- is disrupted in patients with homozygous B3GALTL variants in contrast with their heterozygous relatives. The c.660+1G>A variant was not detected in 455 control chromosomes and is reported at a frequency of is 0.00104 in the non-Finnish European population of the Exome Aggregation Consortium. Based on the collective evidence and the potential impact of splice donor variants the c.660+1G>A variant is classified as pathogenic for Peters plus syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Genetics and Molecular Pathology, SA Pathology | Dec 13, 2021 | The B3GLCT c.660+1G>A variant is classified as PATHOGENIC (PS4, PVS1) The B3GLCT c.660+1G>A variant is located in a splice donor region (PVS1). This recurrent variant has been identiified in both a homozygous and comound heterozygous state in multiple individuals with Peters-plus syndrome (PMID:16909395) (PS4). This variant is in dbSNP (rs80338851) and has been reported in population databases (gnomAD 122/152076 alleles, no homozygotes). This variant has been reported in ClinVar as pathogenic by other diagnostic laboratories (Variation ID:1264) and is damaging in HGMD for Peters-plus syndrome (CS064369). - |
| Pathogenic, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Oct 12, 2018 | This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1,PM2,PP3. - |
| not provided, no classification provided | literature only | GeneReviews | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 18, 2022 | Variant summary: B3GALTL c.660+1G>A (aka c.1020+1G>A) is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: four predict the variant abolishes a 5' splicing donor site. The variant allele was found at a frequency of 0.00076 in 281510 control chromosomes (gnomAD). The variant, c.660+1G>A, has been reported in the literature in numerous homozygous- and compound heterozygous individuals affected with Peters Plus Syndrome (see e.g. Lesnik_2006, Hess_2008, Wang_2020); the variant was described as a recurrent mutation in many different ethnicities, and was reported as the most frequent disease associated allele. These data indicate that the variant is very likely to be associated with disease. Publications also reported experimental evidence and confirmed that the variant results in the skipping of exon 8, in addition, fucosylation defects were also demonstrated in patients (Lesnik_2006, Hess_2008). Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and all of them classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
| Pathogenic, criteria provided, single submitter | research | UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill | Sep 28, 2021 | - - |
| Pathogenic, no assertion criteria provided | literature only | OMIM | Nov 01, 2009 | - - |
not provided Pathogenic:9
| Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Dec 10, 2014 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jan 01, 2024 | B3GLCT: PVS1, PM2 - |
| Pathogenic, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | Nov 14, 2014 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 06, 2022 | Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; leads to skipping of exon 8, as confirmed by RT-PCR studies (Lesnik Oberstein et al., 2006); Also known as c.1020+1G>A using alternate nomenclature; This variant is associated with the following publications: (PMID: 26684045, 25525159, 19796186, 29096039, 18798333, 16909395, 23161355, 34426522, 31589614, 30577886, 31081795, 32224865, 31795264, 32204707, 33726816, 32732226) - |
| Pathogenic, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | Nov 03, 2021 | - - |
B3GLCT-related disorder Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Aug 04, 2024 | The B3GLCT c.660+1G>A variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant has been reported to be a common pathogenic variant for Peters Plus syndrome in the homozygous or compound heterozygous state (described as c.1020+1 G>A, Lesnik Oberstein. 2006. PubMed ID: 16909395; Reis., 2008. PubMed ID: 18798333). This variant is reported in 0.12% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Variants that disrupt the consensus splice donor site in B3GLCT are expected to be pathogenic. This variant is interpreted as pathogenic. - |
Inborn genetic diseases Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 18, 2024 | The c.660+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 8 of the B3GLCT gene. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. Based on data from gnomAD, the A allele has an overall frequency of 0.076% (214/281510) total alleles studied. The highest observed frequency was 0.122% (157/128666) of European (non-Finnish) alleles. This alteration is the most common mutation in this gene and has been reported in the homozygous and compound heterozygous states in association with Peters plus syndrome; this variant has also been reported as c.1020+1G>A (Lesnik Oberstein, 2006; Wang, 2020). This nucleotide position is highly conserved in available vertebrate species. Functional analysis demonstrated that this splice site variant destroys the canonical splice donor site in intron 8, and leads to skipping of exon 8 as confirmed by RT-PCR studies (Lesnik Oberstein, 2006). In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Based on the available evidence, this alteration is classified as pathogenic. - |
Computational scores
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Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
GERP RS
Splicing
Name
Calibrated prediction
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dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DL_spliceai
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