rs398124589
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1_StrongPM2PP3_StrongPP5_Very_Strong
The NM_183050.4(BCKDHB):c.633+1G>A variant causes a splice donor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000496 in 1,613,544 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Consequence
NM_183050.4 splice_donor
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BCKDHB | NM_183050.4 | c.633+1G>A | splice_donor_variant | ENST00000320393.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BCKDHB | ENST00000320393.9 | c.633+1G>A | splice_donor_variant | 1 | NM_183050.4 | P1 | |||
BCKDHB | ENST00000356489.9 | c.633+1G>A | splice_donor_variant | 1 | P1 | ||||
BCKDHB | ENST00000369760.8 | c.633+1G>A | splice_donor_variant | 3 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152108Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251150Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135754
GnomAD4 exome AF: 0.00000411 AC: 6AN: 1461436Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2AN XY: 727068
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152108Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74298
ClinVar
Submissions by phenotype
Maple syrup urine disease Pathogenic:5
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Aug 16, 2019 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | National Newborn Screening Laboratory, Hospital Nacional de Niños | - | This variant is located within the ±2 bp from a splice site in the BCKDHB gene, where loss of function is a known mechanism of disease. It is present in population databases in low frequency (GnomAD exomes: 0,00001; TopMed: 0,00002). This variant has been published in the literature associated with individuals with MSUD (PMID: 27507644, 31119508). It was found in a compound heterozygous state with a known pathogenic variant in a patient with MSUD phenotype. - |
Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Nov 07, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 24, 2024 | This sequence change affects a donor splice site in intron 5 of the BCKDHB gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs398124589, gnomAD 0.006%). Disruption of this splice site has been observed in individual(s) with maple syrup urine disease (MSUD) (PMID: 8312380, 27507644). ClinVar contains an entry for this variant (Variation ID: 96602). Studies have shown that disruption of this splice site results in skipping of exons 5-6 and introduces a premature termination codon (PMID: 8312380). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 08, 2021 | Variant summary: BCKDHB c.633+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. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 1.2e-05 in 251150 control chromosomes. c.633+1G>A has been reported in the literature in two individuals affected with Maple Syrup Urine Disease, in the homozygous state (Abiri_2017, Abiri_2019). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jul 01, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Aug 23, 2013 | - - |
Maple syrup urine disease type 1A Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Dec 13, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at