rs796052135
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong
The NM_001918.5(DBT):c.1018-550A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000329 in 152,190 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_001918.5 intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
DBT | ENST00000370132.8 | c.1018-550A>G | intron_variant | Intron 8 of 10 | 1 | NM_001918.5 | ENSP00000359151.3 | |||
DBT | ENST00000681617.1 | c.1144-550A>G | intron_variant | Intron 9 of 11 | ENSP00000505544.1 | |||||
DBT | ENST00000681780.1 | c.475-550A>G | intron_variant | Intron 9 of 11 | ENSP00000505780.1 |
Frequencies
GnomAD3 genomes AF: 0.0000329 AC: 5AN: 152190Hom.: 0 Cov.: 32
GnomAD4 genome AF: 0.0000329 AC: 5AN: 152190Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74350
ClinVar
Submissions by phenotype
Maple syrup urine disease Pathogenic:3Uncertain:1
Variant summary: DBT c.1018-550A>G is located at a deep intronic position, not widely known to affect splicing. Several computational tools predict a significant impact on normal splicing: three predict the variant creates a 5' donor site. The variant allele was found at a frequency of 3.3e-05 in 150962 control chromosomes (gnomAD v3.1 genomes dataset). c.1018-550A>G has been reported in the literature in a homozygous individual affected with Maple Syrup Urine Disease (Tsuruta_1998). The authors of this study reported experimental evidence and demonstrated that the level of the DBT protein was considerably decreased in patient derived LCLS, in addition, they found inclusion of intronic sequence in patient derived cDNA, which was predicted to result in a truncated protein. These findings were confirmed in an in vitro assay system, where generation of a pseudoexon was demonstrated, resulting in aberrant splicing in vitro (Tsuruta_1998). These data indicate that the variant is likely associated with disease. Two ClinVar submitters have assessed the variant since 2014,, and classified the variant as likely pathogenic or uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic. -
This sequence change falls in intron 8 of the DBT gene. It does not directly change the encoded amino acid sequence of the DBT protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with maple syrup urine disease (PMID: 9621512). ClinVar contains an entry for this variant (Variation ID: 11946). Studies have shown that this variant results in an insertion between exons 8 and 9 and introduces a premature termination codon (PMID: 9621512). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. -
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Maple syrup urine disease type 2 Pathogenic:2
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DBT-related disorder Pathogenic:1
The DBT c.1018-550A>G variant is predicted to interfere with splicing. This variant was reported in the homozygous or compound heterozygous states in individuals with maple syrup urine disease (Tsuruta et al. 1998. PubMed ID: 9621512; Soriano-Sexto et al. PubMed ID: 36361642). In vitro analysis indicated that this substitution created a new 5' splice site and caused an insertion of 126 nucleotides between exons 8 and 9, resulting in a truncated protein (Tsuruta et al. 1998. PubMed ID: 9621512; Vorechovsky et al. 2010. PubMed ID: 19823873). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as likely pathogenic. -
Maple syrup urine disease type 1A Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at