rs1553230703
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP3_ModeratePP5
The NM_001918.5(DBT):āc.788T>Cā(p.Met263Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,459,154 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M263V) has been classified as Uncertain significance.
Frequency
Consequence
NM_001918.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DBT | NM_001918.5 | c.788T>C | p.Met263Thr | missense_variant | 7/11 | ENST00000370132.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DBT | ENST00000370132.8 | c.788T>C | p.Met263Thr | missense_variant | 7/11 | 1 | NM_001918.5 | P1 | |
DBT | ENST00000370131.3 | c.788T>C | p.Met263Thr | missense_variant | 7/8 | 1 | |||
DBT | ENST00000681617.1 | c.788T>C | p.Met263Thr | missense_variant | 7/12 | ||||
DBT | ENST00000681780.1 | c.245T>C | p.Met82Thr | missense_variant | 8/12 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 0.00000206 AC: 3AN: 1459154Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0AN XY: 726144
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Maple syrup urine disease Pathogenic:1Uncertain:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jul 25, 2022 | Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt DBT protein function. ClinVar contains an entry for this variant (Variation ID: 552494). This missense change has been observed in individual(s) with maple syrup urine disease (PMID: 16786533). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 263 of the DBT protein (p.Met263Thr). This variant disrupts the p.Met263 amino acid residue in DBT. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19480318). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Jun 21, 2017 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at