rs587783008
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP5
The NM_001370658.1(BTD):c.250-15del variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000384 in 1,563,456 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000035 ( 0 hom. )
Consequence
BTD
NM_001370658.1 splice_polypyrimidine_tract, intron
NM_001370658.1 splice_polypyrimidine_tract, intron
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.977
Genes affected
BTD (HGNC:1122): (biotinidase) The protein encoded by this gene functions to recycle protein-bound biotin by cleaving biocytin (biotin-epsilon-lysine), a normal product of carboxylase degradation, resulting in regeneration of free biotin. The encoded protein has also been shown to have biotinyl transferase activity. Mutations in this gene are associated with biotinidase deficiency. Multiple transcript variants encoding different isoforms have been described. [provided by RefSeq, Aug 2013]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 3 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
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Variant 3-15641892-AT-A is Pathogenic according to our data. Variant chr3-15641892-AT-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 156006.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=3, Uncertain_significance=1, Pathogenic=1}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BTD | NM_001370658.1 | c.250-15del | splice_polypyrimidine_tract_variant, intron_variant | ENST00000643237.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BTD | ENST00000643237.3 | c.250-15del | splice_polypyrimidine_tract_variant, intron_variant | NM_001370658.1 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152232Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000828 AC: 2AN: 241528Hom.: 0 AF XY: 0.00000767 AC XY: 1AN XY: 130346
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GnomAD4 exome AF: 0.00000354 AC: 5AN: 1411224Hom.: 0 Cov.: 25 AF XY: 0.00000284 AC XY: 2AN XY: 704266
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GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152232Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74390
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:5Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Biotinidase deficiency Pathogenic:5Uncertain:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | May 25, 2023 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 13, 2023 | Variant summary: BTD c.250-15delT, also referred to as c.310-15delT, alters a nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: One predicts the variant creates a 3' acceptor site, two predict the variant weakens a canonical 3' acceptor site, and one predicts the variant has no significant impact on splicing. However, a functional study found no evidence that the variant impacts splicing (Li_2014). The variant allele was found at a frequency of 8.3e-06 in 241528 control chromosomes (gnomAD). c.250-15delT has been reported in the literature in the compound heterozygous state in individuals affected with partial Biotinidase Deficiency, including at least one case where it was confirmed to be in trans with a pathogenic variant (e.g. Li_2014, Procter_2016, Carvalho_2019, Carvalho_2020). These data indicate that the variant may be associated with disease. Experimental evidence evaluating an impact of the variant found that although it does not appear to impact splicing, the variant may result in decreased mRNA expression (Li_2014). This study found that a patient who was compound heterozygous for the variant and the patient's mother, who was a heterozygous carrier, both exhibited decreased mRNA expression, approximately 40% and 65%, respectively, compared to control individuals. Three ClinVar submitters (evaluation after 2014) cite this variant as uncertain significance, likely pathogenic and pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Molecular Genetics Diagnostic Laboratory, Detroit Medical Center University Laboratories | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 22, 2024 | This sequence change falls in intron 2 of the BTD gene. It does not directly change the encoded amino acid sequence of the BTD protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs587783008, gnomAD 0.01%). This variant has been observed in individual(s) with biotinidase deficiency (PMID: 24797656, 26810761, 30912303). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 156006). Studies have shown that this variant alters BTD gene expression (PMID: 24797656). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | May 29, 2018 | - - |
Computational scores
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DS_AG_spliceai
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DS_AL_spliceai
Position offset: 16
Find out detailed SpliceAI scores and Pangolin per-transcript scores at