rs398123486
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2PM5PP3_StrongPP5_Very_Strong
The NM_000709.4(BCKDHA):c.1037G>A(p.Arg346His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000374 in 1,606,188 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R346C) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000709.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BCKDHA | NM_000709.4 | c.1037G>A | p.Arg346His | missense_variant | 8/9 | ENST00000269980.7 | |
BCKDHA | NM_001164783.2 | c.1034G>A | p.Arg345His | missense_variant | 8/9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BCKDHA | ENST00000269980.7 | c.1037G>A | p.Arg346His | missense_variant | 8/9 | 1 | NM_000709.4 | P1 | |
BCKDHA | ENST00000457836.6 | c.1046G>A | p.Arg349His | missense_variant | 8/9 | 2 | |||
BCKDHA | ENST00000542943.5 | c.950G>A | p.Arg317His | missense_variant | 7/7 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152128Hom.: 0 Cov.: 33
GnomAD4 exome AF: 0.00000275 AC: 4AN: 1454060Hom.: 0 Cov.: 35 AF XY: 0.00000415 AC XY: 3AN XY: 722526
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152128Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74310
ClinVar
Submissions by phenotype
Maple syrup urine disease Pathogenic:3Uncertain:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Nov 29, 2021 | - - |
Likely pathogenic, no assertion criteria provided | research | Shieh Lab, University of California, San Francisco | Oct 19, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 07, 2023 | 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 BCKDHA protein function. For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg346 amino acid residue in BCKDHA. Other variant(s) that disrupt this residue have been observed in individuals with BCKDHA-related conditions (PMID: 16786533, 21844576, 22593002), which suggests that this may be a clinically significant amino acid residue. ClinVar contains an entry for this variant (Variation ID: 93336). This missense change has been observed in individual(s) with BCKDHA-related conditions (PMID: 16786533). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 346 of the BCKDHA protein (p.Arg346His). - |
Uncertain significance, no assertion criteria provided | clinical testing | Counsyl | Jul 05, 2017 | - - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jun 14, 2017 | - - |
Maple syrup urine disease type 1A Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Nov 22, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at