rs1085307058
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_183050.4(BCKDHB):c.368del(p.Pro123HisfsTer107) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 31)
Consequence
BCKDHB
NM_183050.4 frameshift
NM_183050.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 7.55
Genes affected
BCKDHB (HGNC:987): (branched chain keto acid dehydrogenase E1 subunit beta) This gene encodes the E1 beta subunit of branched-chain keto acid dehydrogenase, which is a multienzyme complex associated with the inner membrane of mitochondria. This enzyme complex functions in the catabolism of branched-chain amino acids. Mutations in this gene have been associated with maple syrup urine disease (MSUD), type 1B, a disease characterized by a maple syrup odor to the urine in addition to mental and physical retardation and feeding problems. Alternative splicing at this locus results in multiple transcript variants. [provided by RefSeq, Jan 2016]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 6-80167698-AC-A is Pathogenic according to our data. Variant chr6-80167698-AC-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 225303.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BCKDHB | NM_183050.4 | c.368del | p.Pro123HisfsTer107 | frameshift_variant | 4/10 | ENST00000320393.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BCKDHB | ENST00000320393.9 | c.368del | p.Pro123HisfsTer107 | frameshift_variant | 4/10 | 1 | NM_183050.4 | P1 | |
BCKDHB | ENST00000356489.9 | c.368del | p.Pro123HisfsTer107 | frameshift_variant | 4/11 | 1 | P1 | ||
BCKDHB | ENST00000369760.8 | c.368del | p.Pro123HisfsTer93 | frameshift_variant | 4/6 | 3 |
Frequencies
GnomAD3 genomes ? Cov.: 31
GnomAD3 genomes
?
Cov.:
31
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome ? Cov.: 31
GnomAD4 genome
?
Cov.:
31
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Maple syrup urine disease Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Nov 07, 2021 | - - |
Likely pathogenic, criteria provided, single submitter | reference population | Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center | Mar 18, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Mar 17, 2020 | For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in BCKDHB are known to be pathogenic (PMID: 16786533, 22593002). This variant has not been reported in the literature in individuals with BCKDHB-related conditions. ClinVar contains an entry for this variant (Variation ID: 225303). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Pro123Hisfs*107) in the BCKDHB gene. It is expected to result in an absent or disrupted protein product. - |
Computational scores
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Calibrated prediction
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Prediction
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at