rs768832921
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001918.5(DBT):c.75_76del(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 Likely 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
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DBT | NM_001918.5 | c.75_76del | p.Cys26TrpfsTer2 | frameshift_variant | 2/11 | ENST00000370132.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DBT | ENST00000370132.8 | c.75_76del | p.Cys26TrpfsTer2 | frameshift_variant | 2/11 | 1 | NM_001918.5 | P1 | |
ENST00000648283.1 | n.62-8604_62-8603del | intron_variant, non_coding_transcript_variant |
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:8
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 30, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Aug 11, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Dec 24, 2019 | 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Aug 16, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Nov 07, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Genomic Research Center, Shahid Beheshti University of Medical Sciences | Dec 18, 2017 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Department Of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos University | Dec 30, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 08, 2023 | 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. - |
Maple syrup urine disease type 2 Pathogenic:3
Pathogenic, no assertion criteria provided | literature only | OMIM | Feb 01, 1993 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Knight Diagnostic Laboratories, Oregon Health and Sciences University | Mar 18, 2019 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Feb 23, 2015 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at