chr1-100240859-CAT-C
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001918.5(DBT):c.75_76delAT(p.Cys26TrpfsTer2) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000508 in 1,613,208 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. T25T) has been classified as Likely benign.
Frequency
Consequence
NM_001918.5 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000394 AC: 6AN: 152170Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000677 AC: 17AN: 251058Hom.: 0 AF XY: 0.0000590 AC XY: 8AN XY: 135698
GnomAD4 exome AF: 0.0000520 AC: 76AN: 1461038Hom.: 0 AF XY: 0.0000454 AC XY: 33AN XY: 726852
GnomAD4 genome AF: 0.0000394 AC: 6AN: 152170Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74342
ClinVar
Submissions by phenotype
Maple syrup urine disease Pathogenic:6
Variant summary: DBT c.75_76delAT (p.Cys26TrpfsX2) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 6.8e-05 in 251058 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in DBT causing Maple Syrup Urine Disease (6.8e-05 vs 0.0012), allowing no conclusion about variant significance. c.75_76delAT has been reported in the literature in individuals affected with Maple Syrup Urine Disease (example: Pode-Shakked_2020). These data indicate that the variant is likely to be associated with disease. The following publication has been ascertained in the context of this evaluation (PMID: 32151765). ClinVar contains an entry for this variant (Variation ID: 11950). Based on the evidence outlined above, the variant was classified as pathogenic. -
This sequence change creates a premature translational stop signal (p.Cys26Trpfs*2) in the DBT gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DBT are known to be pathogenic (PMID: 16579849, 16786533). This variant is present in population databases (rs768832921, gnomAD 0.03%). This premature translational stop signal has been observed in individuals with maple syrup urine disease (PMID: 8430702, 14517957, 16468966, 20639189, 28417071). ClinVar contains an entry for this variant (Variation ID: 11950). For these reasons, this variant has been classified as Pathogenic. -
NM_001918.3(DBT):c.75_76delAT(C26Wfs*2) is classified as pathogenic in the context of maple syrup urine disease type II. Sources cited for classification include the following: PMID 8430702. Classification of NM_001918.3(DBT):c.75_76delAT(C26Wfs*2) is based on the following criteria: The variant causes a premature termination codon that is expected to be targeted by nonsense-mediated mRNA decay and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening. -
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Maple syrup urine disease type 2 Pathogenic:4
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Maple syrup urine disease type 1A Pathogenic:3
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The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.006%). Predicted Consequence/Location: Frameshift: predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000011950 /PMID: 8430702). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -
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not provided Pathogenic:1
Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 24394677, 32193832, 34671977, 32151765, 31980395, 31980526, 31589614, 32712949, 8430702, 16468966, 34556729, 20639189, 16786533, 14517957, 28417071) -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at